Method and device for ocular alignment and coupling of ocular structures

ABSTRACT

Embodiments provide method and systems for determining or measuring objective eye alignment in an external-coordinate system so as to define a reference axis. Additional embodiments provide a method and system of aligning an objectively determined reference axis of the eye in a selected relationship to a therapeutic axis of an ophthalmic therapeutic apparatus and/or a diagnostic axis of an ophthalmic diagnostic apparatus. Embodiments provide a method and system for planning an ophthalmic treatment procedure based on objective eye alignment in an external-coordinate system so as to define a reference axis of an eye to be treated. The reference axis may be used to position a therapeutic energy component, for example, an orthovoltage X-ray treatment device, e.g., positioned to provide treatment to tissue on the retina, such as the macula.

This application claims the benefit of priority to U.S. ProvisionalPatent Application No. 61/016,472 filed Dec. 23, 2007 and No. 61/020,655filed Jan. 11, 2008. This application also claims priority as acontinuation-in-part of U.S. patent application Ser. No. 12/027,069,Ser. No. 12/027,083, and Ser. No. 12/027,094, each filed Feb. 6, 2008.Each of the above applications is incorporated herein in its entirety byreference.

In addition, each of the following commonly-owned US applications areincorporated by reference in their entirety: No. 60/933,220 filed Jun.4, 2007; Ser. No. 11/879,843 filed Jul. 18, 2007; Ser. No. 11/879,901filed Jul. 18, 2007; Ser. No. 11/833,939 filed Aug. 3, 2007; Ser. No.11/873,386 filed Oct. 16, 2007; Ser. No. 12/023,954 filed Jan. 31, 2008;Ser. No. 12/023,905 filed Jan. 31, 2008; Ser. No. 12/023,968 filed Jan.31, 2008; Ser. No. 12/024,934 filed Feb. 1, 2008; Ser. No. 12/023,884filed Jan. 31, 2008; and Ser. No. 12/026,507 filed Feb. 5, 2008; andSer. No. 12/100,398 filed Apr. 9, 2008.

FIELD OF THE INVENTION

The invention relates to systems and methods for aligning the eye of asubject. More specifically, the invention relates to providing animaging system and a method of use of an imaging system for determiningobjective eye alignment.

BACKGROUND OF THE INVENTION

Accurate alignment of a subject's eye is important in a number ofsituations. For example, when taking certain types of eye measurements,it is critical to know that the eye is in a particular referenceposition. When measuring the cornea of a patient's eye beforetherapeutic treatment, it can be important to repeat those measurementsafter the treatment to determine how much, if any, the treatment hasaffected the measurements. In order to accomplish this, one must ensurethat the eye alignment is in the same position each time the particularmeasurements are made. Otherwise, the difference in data from before andafter the treatment might be due to a change in eye alignment ratherthan the treatment.

In addition to those situations where one needs to ensure that the eyeis aligned in the same position for two or more measurements, there aresituations where eye alignment is desirable for diagnostic measurementsof eye performance. There are situations when a human subject can simplybe requested to fixate on a particular object. Thus, the human may statethat he or she is currently looking at a light source, thereby providing“subjective” eye alignment information. However, there are situationswhere a physician or researcher would like “objective” eye alignmentinformation indicating the orientation of the eye and, to the extentpossible, indicating what the eye is viewing.

For example, very young children cannot be relied upon to fixate on suchan object for measurements, such as refraction measurements which arevery desirable to ensure that “in focus” images are being received whenthe child's brain is learning to interpret images. Likewise, adultssubjected to extended eye examinations may become tired or subject toother duress and fail to maintain reliable fixation. A patient who issubjected to a therapeutic process such as laser ablation eye surgerymay not be able to maintain desired eye orientation over an extendedtreatment time because of applied anesthesia, fatigue, or distraction bythe procedure. Further, a research animal typically cannot be trained tofixate during eye measurements.

In each of the above cases, the failure or inability of the subject tomaintain eye fixation upon an object can produce eye measurements ortreatments that are seriously in error. Therefore, there are situationswhere absolute eye alignment data is needed (i.e., the eye is aligned ina certain manner) and situations where comparative eye alignment data(i.e., the eye is in the same alignment as when earlier measurementswere taken) are needed and one cannot rely upon a subject maintainingthe alignment.

A high level of accuracy is often required when performing surgery orother treatment on a part of the body that is subject to involuntarymovement. It is typically a problem to align a patient's eye. The eye ispredisposed to saccades, which are fast, involuntary movements of smallmagnitude. A patient may voluntarily shift their gaze during surgery,and furthermore, eye position stability is affected by the patient'sheartbeat and other physiological factors. Moreover, there is stilldebate regarding the proper reference axis for alignment of the eye fortreatment, such as laser refractive surgery.

In typical laser ophthalmic systems for treatment of defects orconditions, an eyetracker component of the system is utilized to trackthe motion of the eye during surgery, and to interrupt delivery of thetherapeutic treatment when tracking cannot be maintained. Often, thesurgeon will engage an eye tracker manually when it appears to beproperly aligned. This subjective technique is prone to error which maylead to decentered ablations and other impediments to satisfactoryvision correction. Various eye tracker technologies are commerciallyavailable. In some embodiments of the present invention described below,it is desirable to engage an eye tracker when it is locked onto thedesired reference point on the eye.

Various types of visual axis detecting devices have been proposed. Forexample, some visual axis detecting devices are based on the patient'sgaze. Japanese Patent Publication 1-274736, for example, describes adevice which projects parallel light beams to an eyeball of an observerfrom a light source and determines a visual axis by making use of animage reflected from a cornea, that is, a cornea reflected image, orPurkinje image, and the imaging position of a pupil.

Thus, there is a need for more reliability and accuracy in eyealignment, particularly as it relates to eye treatment methods such aslaser ophthalmic surgery.

SUMMARY OF THE INVENTION

Accordingly, it is an object of the invention to provide a method andsystem of determining or measuring objective eye alignment in anexternal-coordinate system so as to define a reference axis of asubject's eye. It is another object of the invention to provide a methodand system of aligning an objectively determined reference axis of theeye in a selected relationship to a therapeutic axis of an ophthalmictherapeutic apparatus and/or a diagnostic axis of an ophthalmicdiagnostic apparatus.

It is another object of the invention to provide an eye tracking methodand system to monitors the movement of a patient's eye during anophthalmic procedure, wherein the eye tracker system is automaticallyengaged upon determining objective eye alignment in an externalcoordinate system.

It is yet another object of the invention to provide a method and systemfor planning an ophthalmic treatment procedure based, at least in part,on objective eye alignment in an external-coordinate system so as todefine a reference axis of an eye to be treated. It is yet anotherobject of the invention to provide an ophthalmic treatment method andsystem, wherein a therapeutic energy component is controlled in one ormore operative respects based on upon determining objective eyealignment in an external coordinate system.

It is yet another object of the invention to provide an ophthalmictreatment method and system, wherein a therapeutic energy component ispositioned and/or stabilized with respect to a reference axis of an eyeto be treated, defined by objective eye alignment in an externalcoordinate system. It is yet another object of the invention to providean ophthalmic treatment method and system, wherein an objectivelydetermined reference axis of an eye to be treated is positioned and/orstabilized with respect to a therapeutic energy component.

It is yet another object of the invention to provide an ophthalmictreatment system, wherein a therapeutic energy component is controlledin one or more operative respects based on upon determining objectiveeye alignment in an external coordinate system.

In one embodiment having aspects of the invention, a method is providedfor determining when a subject's eye position is aligned with areference axis in an external coordinate system, wherein the methodcomprises determining positions of the limbus (the generally circularsclera/cornea boundary) of the subject's eye in the external coordinatesystem, and from these positions, determining the center of the limbusin the external-coordinate system. The method further comprisesdetermining the position of an image of a light beam reflected from thepatient's eye (e.g., the cornea), and determining that the subject's eyeis aligned with the reference axis when the determined position of thereflection is coincident with the determined center of the limbus.

In embodiments of this method, the determinations of limbus center andcorneal reflection may be carried out with the patient's head stabilizedin a head restraint, and may be carried out by an imaging systemdisposed in the external coordinate system. For example, the method mayinclude recording an image of the subject's limbus by an opticaldetector, fitting the limbus image to a circle, and determining theposition of the center of the circle with respect to the externalcoordinate system.

In some embodiments of this method, the reflection from the patient'seye is a first Purkinje image formed by reflection of a coherent orfocused light beam off the anterior surface of the cornea. For example,the optical axis of the coherent or focused light beam may be alignedwith the reference axis.

Some embodiments of this method include generating an eye-alignmentsignal when the subject's eye position is aligned with anexternal-coordinate reference axis. As an example, a signal may begenerated upon a determination that the position of the cornealreflection is coincident with the center of the limbus. The method mayinclude using this signal as an element of a procedure, such as usingthe eye-alignment signal to attach an ocular positioning and stabilizingdevice to the subject's eye; and/or using the eye-alignment signal toactivate a therapeutic beam aimed along a path having a knownrelationship with the external-coordinate reference system. In someembodiments, the method is used in treating macular degeneration, forexample wherein the therapeutic beam includes one or more low-energycollimated X-ray beams, which are aimed along a path that intersects thereference axis at a selected region of the subject's eye, e.g. at anintersection angle of between about 10 to about 45 degrees.

In some embodiments, the reference axis may define a geometric axis ofthe patient eye, and the method may include calculating the distancebetween the cornea and the retina along this axis.

In some embodiments, the method may be applied to determine the positionof intersection of the reference axis with the patient's retina relativeto a structure of interest on the retina. Additional steps may includedetermining the position of an image formed by a light beam reflectedfrom the retina of the patient's eye. For example, a light beam used toobtain an anterior eye reflection, such as a first Purkinje image, mayalso be used to illuminate the retina, so as to obtain a retinalreflection image, such as when a first Purkinje image is coincident withthe center of the limbus image and thus the retinal reflection image isaligned with the reference axis. Further, a second coherent or focusedlight beam may be passed through the pupil of the subject's eye toreflect off a structure of interest in the retina, and the position ofthe image of the reflection of the second beam off the structure ofinterest may be determined in the external coordinate system, relativeto the axis of reference.

In yet another embodiment having aspects of the invention, a method isprovided for defining a reference axis of a patient's eye in an externalcoordinate system, wherein the method comprises determining positions ofthe limbus of the patient's eye in the external coordinate system, andfrom these positions, determining the center of the limbus in theexternal-coordinate system. The method further comprises determining theposition of an image of a light beam reflected from the cornea of thepatient's eye, and adjusting the position of the eye until the positionof the reflection is coincident with the center of the limbus, at whichposition an axis normal to the cornea at the corneal center defines thepatient reference axis.

In some embodiments, the reference axis defined by the method extendsfrom the cornea to a position on the retina which is a maximum distancefrom the cornea. The method may further include superimposing thepatient reference axis on a three-dimensional model of the eye byaligning the patient reference axis with a model reference axis. In someembodiments, the method may be applied for conducting a diagnostic ortherapeutic procedure on the eye, the method further includingpositioning a beam of a diagnostic or therapeutic device at a selectedposition and angle with respect to the patient reference axis.

Some embodiments of this method include generating an eye-alignmentsignal when the patient's eye position is aligned with anexternal-coordinate reference axis. The method may include using thissignal to attach an ocular positioning and stabilizing device to thesubject's eye. Alternatively or additionally, the method may includeusing the eye-alignment signal to activate a therapeutic beam aimedalong a path having a known relationship with the external-coordinatereference system. In some embodiments, the method is used in treatingmacular degeneration, for example wherein the therapeutic beam is alow-energy collimated x-ray beam, and the therapeutic beam is aimedalong a path that intersects the reference axis in a macular region ofthe subject patient's eye, and at an angle between about 10-45 degreeswith respect to the reference axis.

In some embodiments, the method may be applied to determine the positionof intersection of the reference axis with the patient's retina relativeto a structure of interest on the retina, including determining theposition of an image formed by a light beam reflected from the retina ofthe patient's eye, when a corneal refection of the light beam iscoincident with the center of the limbus. Further, a second coherent orfocused light beam may be passed through the pupil of the subject's eyeto reflect off a structure of interest in the retina, and the positionof the image of the reflection off the structure of interest may bedetermined in the external coordinate system.

In yet another embodiment having aspects of the invention, a system isprovided of defining a reference axis of a patient's eye in an externalcoordinate system, wherein the system comprises (a) a head support forsupporting the patient's head, (b) a light source for illuminating thesclera/cornea boundary (limbus) of the patient's eye, (c) a light sourcefor directing a coherent or focused light beam on the cornea of thepatient's eye, (d) an imaging system for recording an image of thepatient's limbus and an image formed by reflection of the coherent orfocused light beam from the cornea of the patient's eye, and (e) aprocessor operatively connected to the imaging system for (i) from theimage of the sclera/cornea boundary, determining the center of thelimbus of the patient's eye in the external-coordinate system, and (ii)from the image of the reflection of the coherent or focused light beamoff the cornea, determining when the position of the reflection image iscoincident with the center of the limbus image, at which position anaxis normal to the cornea at the corneal center defines the referenceaxis.

In some system embodiments, the light source for illuminating the limbusis effective to illuminate the entire eye, and the light source fordirecting a coherent or focused light beam on the cornea is a coherentlight beam. In some system embodiments, the imaging system includes aCCD photodetector. In some system embodiments, the processor operates tofit the image of the limbus to a circle, and find the center of thecircle. Further, the processor may operate to determine, at each eyeposition of the patient eye, whether the center of the patient eyelimbus is the same as the position of the reflection image from thecornea. In some system embodiments, the processor may operate togenerate a signal when the position of the reflection image iscoincident with the center of the limbus image. Further, the processormay operate to generate positioning signals for positioning a diagnosticor therapeutic device at a selected position and angle with respect tothe reference axis.

In some embodiments, the system further operates to record reflectionsof a coherent or focused beam off of the surface of the retina, whereinthe processor further operates to (iii) determine the position of animage formed by reflection of the light beam off the retina, when theposition of the reflection image off the cornea is coincident with thecenter of the limbus image, (iv) determine the position of an imageformed by reflection of another coherent or focused light beam off aselected structure of interest in the retina, and (v) determine theposition of the image of the reflection of the other beam off thestructure of interest in the external coordinate system, relative to theposition of the image of the reflection off the retina along thereference axis.

In yet another embodiment having aspects of the invention, a method ofis of placing a patient's eye in alignment with a reference axis in anexternal coordinate system is provided, comprising (a) placing an ocularguide on a patient's eye, (b) centering the guide with respect to thesclera/cornea boundary of the patient's eye, (c) stabilizing the ocularguide on the eye by applying a negative pressure between the guide andeye, (d) moving the ocular guide, and thus patient's eye, until theocular guide is aligned with the reference axis, thus to place thepatient's eye in alignment with the reference axis. The ocular guide mayhave a peripheral ring dimensioned to be contained within orsubstantially coincident with the sclera/cornea boundary of thepatient's eye, and step (b) may include adjusting the position of theguide until the peripheral ring and sclera/cornea boundary are coaxiallyaligned.

In yet another embodiment having aspects of the invention, animage-guided ocular treatment system is provided, comprising (a) a headsupport for supporting a patient's head, (b) a eye guide adapted to beplaced on the patient's eye, and stabilized on the eye by theapplication of negative pressure between the eye guide and eye when theguide is approximately centered with respect the sclera/cornea boundaryof the patient's eye, (c) a camera for recording an image of the eyeguide on the patient's eye, (d) a guide-alignment assembly for detectingalignment between the eye guide, with such stabilized on a patient'seye, and an external-coordinate reference axis, (e) an external armpivotally attached to the eye guide to hold the eye at a position inwhich the eye guide is aligned with the external-coordinate referenceaxis, (e) a processor operatively connected to the camera andguide-alignment assembly for (i) determining from the image of eye guideand the sclera/cornea boundary, any variation from true centering of theeye guide on the patient's eye, (ii) if variation from true centering isdetermined, constructing a coordinate transform between the actual andcentered positions of the eye guide, (iii) with the eye guide moved toand held at its aligned position, and applying the coordinate transformif necessary, determining the position of the eye with respect to theexternal-coordinate reference axis, (iv) from the determination in step(iii) determining a treatment axis or axes along which a therapeuticbeam will be aimed at a target region of the eye, and (f) a displaymonitor operatively connected to the processor for displaying to theuser, an image of the patient's eye and attached eye guide, informationabout the extent of alignment between the eye guide and reference beam,and a virtual image of the treatment axis or axis.

In some embodiments, the processor may include stored fundus images, andoperates to superimpose those images on the image of the patient's eyedisplayed on the monitor, allowing the user to view the areas ofintersection of the therapeutic beam axes and fundus.

These and other objects and features of the invention will be more fullyappreciated when the following detailed description of the invention isread in conjunction with the accompanying figures.

BRIEF DESCRIPTION OF THE FIGURES

The figures and the associated descriptions are provided to illustrateembodiments of the disclosure and not to limit the scope of thedisclosure. Throughout the figures, reference numbers are reused toindicate correspondence between referenced elements. The figures are insimplified form and are not necessarily precise in scale. In referenceto the disclosure herein, for purposes of convenience and clarity only,directional terms, such as top, bottom, left, right, up, down, over,above, below, beneath, rear, and front are used with respect to theaccompanying figures. Such directional terms are not to be construed aslimiting the scope of the invention in any manner.

The particular figures may be briefly summarized as follows:

FIG. 1 illustrates a schematic side view of an anterior portion of aneye in association with an embodiment of an alignment system havingaspects of the invention.

FIG. 2 is an exemplary plot of a co-alignment detection signalindicative of coincident reflection of the first Purkinje reflex and thecenter of the limbus.

FIGS. 3A and 3B illustrate exemplary ophthalmic treatment systems havingaspects of the invention, including a treatment device which ispositioned and/or controlled by an eye positioning/stabilizing device.

FIGS. 3C and 3D illustrate exemplary ophthalmic treatment system forX-ray treatment of the retina, wherein FIG. 3C a cross-sectional view ofan eye taken along the geometric axis in a horizontal plane, and FIG. 3Dis a detail frontal view of an eye as seen aligned with a systemreference axis.

FIGS. 4A-B and 5A-B illustrate exemplary eye positioning and/orstabilizing devices having aspects of the invention.

FIGS. 6A-C illustrate schematic side views of an anterior portion of aneye in three orientations with respect to an embodiment of an alignmentsystem having aspects of the invention, depicting a method utilizinglimbus sizing to define the reference axis.

FIG. 7 is a diagram of an exemplary method having aspects of theinvention, showing a sequence of the successive data processing stepsused to identify the limbic boundary and limbic center.

FIGS. 8A-B illustrate a reference axis defined in an embodiment of analignment system having aspects of the invention, oriented so that thecenter of collimated light reflection from the retina coincides with thecenter of the limbus.

FIGS. 9A-B illustrate an embodiment of an alignment system generallysimilar to that of FIGS. 8A-B, in which the center of collimated lightreflection from the retina is now off-center or off-axis with respect tothe center of the limbus.

FIG. 10 depicts an embodiment of an alignment system having aspects ofthe invention, including beam splitters to superimpose the reflection ofa laser beacon aligned with a reference axis upon the image obtained ofa subject's retina by a fundus camera.

FIGS. 11A-B show a pair of fundus images obtained with the system as inFIG. 10, wherein FIG. 11A depicts an image in which the focus of thelaser beacon and the laser beacon reflection are aligned with the centerof the limbus, and FIG. 11A depicts an image in which the beacon is notaligned with the center of the limbus.

FIGS. 12A-B depict a summary of the methodology system having aspects ofthe invention, adapted to be used to deliver radiation therapy to themacula of a patient, wherein FIG. 12A is a diagram of the treatmentsystem FIG. 12B shows a fundus image of the subject retina.

FIGS. 13A-C depict x-ray therapy beams traveling through an eye to atherapy center or target, wherein FIG. 13A shows in cross section theangular arrangement of the beams, FIG. 13B depicts a retinal image inwhich the radiation therapy center is centered about the treatment axis,and FIG. 13B depicts a retinal image in which the radiation therapycenter is coincident with the macula and not the treatment axis.

FIG. 14 is a diagram of an exemplary method having aspects of theinvention, showing a sequence of the successive steps used to obtain therelationship between the center of the limbus, the optical axis, and therelative position of a beam traveling through the limbus.

FIG. 15 is a diagram of an exemplary system having aspects of theinvention, configured to administer photoablative eye surgery.

FIGS. 16A-F depict alternative species having aspects of the inventionof a “breakaway” post fitting which may be employed with eye positioningand/or stabilizing devices such as shown in FIGS. 4A-B and 5A-B.

FIGS. 17A-17D depict a number of embodiments of eyeholders havingaspects of the invention having alternative configurations of a contactmember.

FIGS. 18A(1)-18B(2) depict embodiments of eyeholders having aspects ofthe invention having alternative configurations of a contact member.

DETAILED DESCRIPTION OF THE INVENTION

Reference will now be made in detail to disclosed embodiments of theinvention, examples of which are illustrated in the accompanyingfigures.

I. DEFINITIONS

Unless otherwise indicated, all technical and scientific terms usedherein have the same meaning as they would to one skilled in the art ofthe present invention. It is to be understood that this invention is notlimited to the particular methodology and protocols described, as thesemay vary.

As used herein, “accommodation” refers to the ability to change focusfrom distant objects to near objects, which ability may tend to diminishwith age.

The term choroid” refers to the highly vascular layer of the eye beneaththe sclera.

As used herein, “ciliary muscle” refers to a muscular ring of tissuelocated beneath the sclera and attached to the lens via zonules.

As used herein, “conjunctiva” refers to the thin, transparent tissuecovering the outside of the sclera. In some embodiments of theinvention, reference is made to one or more devices or systems of theinvention in contact with outer structures of the eye, such as thesclera. In these embodiments, it is to be understood that the device orsystems of the invention may be in contact with the named structure, ormay be in contact with the conjunctiva covering the structure.

As used herein, “cornea” refers to the transparent, avascular tissuethat is continuous with the opaque sclera and semitransparentconjunctiva, and covered by tear film, or corneal epithelium, on itsanterior surface and bathed by aqueous humor on its posterior surface.

As used herein, “limbus” refers to the boundary where the cornea meetsthe sclera.

As used herein, “retina” refers to the light-sensitive layer of tissuethat lines the inner back of the eye and sends visual impulses throughthe optic nerve to the brain.

As used herein “ocular disease” refers to a disease of the eye,including, but not limited to tumors, ocular degeneration,retinopathies, retinitis, retinal vasculopathies, diabeticretinopathies, diseases of the Bruch's membrane and the like.

As used herein, the term “reducing ocular disease” also encompassestreating and alleviating the ocular disease.

As used herein, “sclera” refers to the outer supporting structure, or“white,” of the eye.

As used herein, the term “subject” refers to man or any animal that hasan eye.

As used herein, “vitreous body” refers to the clear colorlesstransparent jelly that fills the eye posterior to the lens and that isenclosed by a hyaloid membrane.

As used herein, “zonules” refers to a circular assembly of radiallydirected collagenous fibers that are attached at their ends to the lensand at their outer ends to the ciliary muscle.

As used herein, the term “presbyopia,” refers to the inability of theeye to focus sharply on nearby objects. Presbyopia is associated withadvancing age and typically entails a decrease in accommodation.Introduction of treatment, e.g., laser ablation, according to any of theimplementations described herein, preferably increases or facilitates anincrease in accommodation, thereby mitigating effects of presbyopia.

The term “radiodynamic therapy” refers to the combination of collimatedx-rays with a concomitantly administered systemic therapy.

The term “radiodynamic agents” is intended to have its ordinary andplain meaning, which includes, without limitation, agents that respondto radiation, such as x-rays, and agents that sensitize a tissue to theeffects of radiation.

The term “photodynamic therapy” refers to a therapeutic or diagnosticmethod involving use of a photoreactive agent and radiation of asufficient intensity and wavelength to activate the photoreactive agent.The activated photoreactive agent then, through emission of energy,exerts a therapeutic effect or allows for diagnosis through detection ofemitted energy.

The term “photodynamic agents” is intended to have its plain andordinary meaning, which includes, without limitation, agents that reactto light and agents that sensitize a tissue to the effects of light.

“Radiation,” as used herein, is intended to have its ordinary meaning,which includes, without limitation, at least any photonic-basedelectromagnetic radiation which covers the range from gamma radiation toradiowaves and includes x-ray, ultraviolet, visible, infrared,microwave, and radiowave energies. Therefore, planned and directedradiotherapy can be applied to an eye with energies in any of thesewavelength ranges.

“Radiotherapy,” as used herein, and is intended to have its ordinarymeaning, which includes, without limitation, at least any type ofclinical therapy that treats a disease by delivery of energy throughelectromagnetic radiation. X-ray radiation generally refers to photonswith wavelengths below about 10 nm down to about 0.01 nm. Gamma raysrefer to electromagnetic waves with wavelengths below about 0.01 nm.Ultraviolet radiation refers to photons with wavelengths from about 10nm to about 400 nm. Visible radiation refers to photons with wavelengthsfrom about 400 nm to about 700 nm. Photons with wavelengths above 700 nmare generally in the infrared radiation regions. Within the x-ray regimeof electromagnetic radiation, low energy x-rays can be referred to asorthovoltage. While the exact photon energies included within thedefinition of orthovoltage varies, for the disclosure herein,orthovoltage refers at least to x-ray photons with energies from about20 keV to about 500 keV.

As used herein, “treatment” refers to any manner in which one or more ofthe symptoms of a disease or disorder are ameliorated or otherwisebeneficially altered. Treatment also encompasses any therapeutic use ofthe systems herein.

Diagnostics can also be performed with any type of energy source ortreatment described herein and may be referred to as “radiationdiagnostics.”

As used herein, the term “global coordinate system” or “externalcoordinate system” refers to a physical world of a machine or room. Theglobal coordinate system is generally a system relating a machine, suchas a computer or other operating device, to the physical world or roomthat is used by the machine. The global coordinate system can be used,for example, to move a machine, components of a machine, or otherelements from a first position to a second position. The globalcoordinate system can also be used, for example, to identify thelocation of a first item with respect to a second item.

“Kerma,” as used herein, refers to the energy released (or absorbed) pervolume of air when the air is hit with an x-ray beam. The unit ofmeasure for Kerma is Gy. Air-kerma rate is the Kerma (in Gy) absorbed inair per unit time. Similarly, “tissue kerma” rate is the radiationabsorbed in tissue per unit time. Kerma is generally agnostic to thewavelength of radiation, as it incorporates all wavelengths into itsjoules reading.

As used herein, the term “radiation dose” is meant to include, withoutlimitation, absorbed energy per unit mass of tissue. One example of ameasure of radiation dose is the Gray, which is equal to 1 joule perkilogram, which generally also equals 100 rad. For example, as usedherein in some embodiments, a radiation dose may be the amount ofradiation, or absorbed energy per unit mass of tissue, that is receivedor delivered during a particular period of time. For example, aradiation dose may be the amount of absorbed energy per unit mass oftissue during a treatment process, session, or procedure.

As used herein, the term “trajectory” is meant to include, withoutlimitation, a general path, orientation, angle, or direction of travel.For example, as used herein in some embodiments, the trajectory of alight beam can include the actual or planned path of the light beam. Insome embodiments, the trajectory of a light beam can be determined by anorientation of a light source that emits the light beam, and thetrajectory can, in some embodiments, be measured, such as by an angle,or determined as with respect to a reference, such as an axis or plane.

As used herein, the term “geometric axis” refers to that axis which isthe axis of symmetry of the eye in the anterior to posterior direction.This axis extends from the center of the cornea through to the center ofthe posterior pole of the eye and is that axis which the eye can berotated around with rotational symmetry. The geometric axis is an axispurely related to ocular anatomy and can be determined in any eye, evenin a blind patient.

As used herein, the term “optical axis” of the eye is taken to begenerally synonymous with the term “geometric axis”.

As used herein, the term “visual axis” is the axis which passes throughthe center of the lens to reach the center of the fovea. It is typicallydetermined when the subject is looking directly at an object, the axisintersecting a region on the fovea. The visual axis is to an extentdetermined by patient-specific visual function, may be affected by eyepathology and adaptive patient behavior, and may be difficult todetermine in some patients.

As used herein, the term “reference axis” refers to an axis whichrelates a subject's ocular anatomy to an external coordinate system,i.e., a coordinate system external to the eye, such as a coordinatesystem defined by an ophthalmologic treatment or diagnostic device (insome instances a reference axis may be referred to herein as an “axis ofinterest”. In the embodiments described in particular detail herein, thereference axis generally is, or accurately approximates and represents,the geometric axis of the eye as referenced in an external coordinatesystem.

However, alternative reference axes may be defined, and it should beunderstood, that many aspects of the invention may be usefully applied,without departing from the spirit of the invention, to systems andmethods in which the axis of interest is different than the geometricaxis. For example, in certain embodiments having aspects of theinvention the “axis of interest” may be the visual axis. Alternativeembodiments may define an eye reference system with respect to a numberof other observable and/or measurable eye structures or properties.Regardless of the eye axis being defined as a reference axis, it can bealigned with respect to an external coordinate system, and may serve asa reference axis for anatomic structures of the eye which may be ofinterest in diagnosis or treatment, such as a macula of the retinaexhibiting macular degeneration.

As used herein, the term “aligned with” means to arrange in a line or soas to be coincident or parallel. In particular, a patient's eye positionis aligned with a reference axis in an external coordinate system whenthe geometric axis of the eye is coincident with the reference axis.

The term “positioned with respect to” is meant to include, withoutlimitation, having a fixed angular relationship between zero and 180degrees. For example, as used herein, two light beams or x-ray beams arepositioned with respect to each other if they are collinear, areoriented with respect to each other at a fixed angle, or have anotherfixed relationship. In some embodiments, the angle between aligned lightbeams or x-ray beams can range from about zero degrees to about 360degrees, and can include about 90 degrees, about 180 degrees, and about270 degrees.

“Beam axis” or “device axis”, as used herein, is meant to include,without limitation, a characteristic directional axis of a treatment ordiagnostic device, for example, an axis of propagation of a collimatedor focused light beam and/or a collimated X-ray beam emitted by a devicefor treatment or diagnosis. in some embodiments, a beam axis may be theaxis of a collimated orthovoltage X-ray beam emitted by an X-ray deviceand used for treating a target tissue in an organ, such as an eye. Suchan embodiment may also emit a collimated or focused laser beam which isco-linear with the X-ray beam, i.e., and also aligned with the beamaxis.

“Treatment axis,” as used herein, is meant to include, withoutlimitation, an axis of an organ or anatomical structure in relation to atreatment device. For example, in some embodiments, the treatment axisof the organ is related, such as by an angle, to an characteristic axisof the treatment device (e.g., the beam axis of a treatmentbeam-emitting device). In some embodiments, the intersection of thetreatment axis and the device axis is used to define the target for theradiotherapy beam.

As used herein, the term “treatment session” is meant to include,without limitation, a single or a plurality of administrations oftherapeutic treatment of a target tissue, e.g., heat therapy and/orradiation therapy. For example, in some embodiments, a treatment sessioncan include a single administration of x-ray beams to the eye. In someembodiments a treatment session can include a plurality ofadministrations of x-ray beams and laser radiation to the subject's eye.In some embodiments, a treatment session is limited to, for example, asingle visit by a patient to a clinic for treatment, and in someembodiments, a treatment session can extend over a plurality of visitsby a patient to the clinic. In some embodiments, a treatment session caninclude a single procedure of administering radiotherapy, and in someembodiments, a treatment session can include a plurality of proceduresfollowing different protocols for each procedure. In some embodiments, atreatment session may be limited to about a single day, and in someembodiments, a treatment session can be about 2 days, about 3 days,about 5 days, about 1 week, about 10 days, about 2 weeks, about 3 weeks,about 1 month, about 6 weeks, about 2 months, about 3 months, about 6months, about 1 year, or longer.

As used herein, the term “treatment period” is meant to include, withoutlimitation, any single or plurality of administrations of radiotherapyor related therapeutic treatment of tissue, and can include a single orplurality of treatment sessions.

As used herein, the term “orders of magnitude, is meant to include,without limitation, a class of scale or magnitude of any amount, whereeach class contains values of a ratio related to the class preceding it.For example, in some embodiments, the ratio relating each class may be10. In these embodiments, one order of magnitude is a magnitude based ona multiple of 10, two orders of magnitude is based on two multiples of10, or 100, and three orders of magnitude is based on three multiples of10, 1000.

“Laser” energy is composed of photons of different energies ranging fromshort wavelengths, such as ultraviolet radiation, up to longwavelengths, such as infrared radiation. Laser refers more to thedelivery mechanism than to the specific wavelength of radiation. Laserlight is considered “coherent” in that the photons travel in phase withone another and with little divergence. Laser light is also collimatedin that it travels with relatively little divergence as it proceeds inspace. Light can be collimated without being coherent (in phase) andwithout being a laser; for example, lenses can be used to collimatenon-x-ray light. X-ray light is typically collimated with the use ofnon-lens collimators, the penumbra defining the degree of successfulcollimation. Laser pointers are typically visualization tools, whereaslarger, higher-flux lasers are utilized for therapeutic applications. Insome embodiments of the systems and methods described herein, optics canbe used, such as lenses or mirrors, and in some embodiments, there areno intervening optical elements, although collimators may be used.

The two eye chambers are the anterior and posterior chambers. Theanterior chamber includes, among other things, the lens, theconjunctiva, the cornea, the sclera, the trabecular apparatus, theciliary bodies, muscles, and processes, and the iris. The posteriorchamber includes, among other structures, the vitreous humor, theretina, and the optic nerve.

“Ocular diseases,” as used in this disclosure, is intended to have itsordinary meaning, which includes, without limitation, at least diseasesof the anterior eye (e.g., glaucoma, presbyopia, cataracts, dry eye,conjunctivitis) as well as diseases of the posterior eye (e.g.,retinopathies, age related macular degeneration, diabetic maculardegeneration, and choroidal melanoma).

Drusen are hyaline deposits in Bruch's membrane beneath the retina. Thedeposits are caused by, or are at least markers of inflammatoryprocesses. They are present in a large percentage of patients over theage of 70. Although causality is not known, drusen are associated withmarkers of the location where inflammation is occurring and whereneovascularization has a high likelihood of occurring in the future;these are regions of so called “vulnerable retina.” Therefore, applyinginflammation-reducing radiation to the region is beneficial, inaccordance with so me embodiments of the invention.

As used herein, Purkinje is a term used to denote a reflected image offa surface of the eye. For example, the first Purkinje refers to thereflection off the anterior surface of the cornea and the secondPurkinje refers to the reflection off the posterior surface of thecornea.

II. EYE ALIGNMENT SYSTEM AND METHOD

One aspect of the invention is directed to systems and methods forobjectively and accurately identifying and aligning a reference axis ofa patient's eye. In the embodiments described in particular detail, thereference axis is, or accurately approximates and represents, thegeometric axis of the eye, and therefore, the terms “geometric axis” and“reference axis” will frequently be used interchangeably. In theseembodiments, the geometric axis of the eye is identified and alignedwith reference to an external coordinate system.

In another aspect of the invention, the aligned eye can then bepositioned relative to the beam axis or device axis of a diagnostic or atherapeutic component whose position is referenced to the commonexternal coordinate system, such as an excimer laser of a refractivevision correction surgery system, an orthovoltage X-ray treatmentsystem, or the like. Typically, the external coordinate system will be a3-dimensional coordinate system for purposes of alignment of the eye,regardless of the particular degrees of freedom of motion that may beincorporated in the structure of a particular associated diagnostic ortherapeutic device.

Aspects of the invention will find utility both in laboratory researchand in clinical application. The advantages of the present invention arenumerous. Exemplary advantages of the systems and methods describedbelow include:

-   (i) providing objective eye alignment information which permits eye    alignment relative to an external point or line, such as an    instrument or device axis, or to provide eye alignment information    by indicating when the present eye alignment is the same as an    earlier eye alignment;-   (ii) providing eye alignment data which can be used in combination    with other diagnostic and therapeutic instruments;-   (iii) allowing eye alignment data to be provided without requiring    instrumentation, such as an eye guide, which could block or prevent    use of diagnostic and/or therapeutic devices which may    advantageously use eye alignment information for improving their    diagnostic and/or therapeutic operations; and-   (iv) allowing one to bring the eye of a subject to a particular    desired alignment, while the subject is under general anesthesia or    is otherwise unable to cooperate in bringing their eye to a    particular alignment, e.g., with use of an eye guide, the eye of a    subject can be brought to a predetermined alignment.

Referring now to the figures, and more particularly to FIG. 1, aschematic side view of an anterior portion of an eye 10 is shown inassociation with a block diagram of an alignment system 100 havingaspects of the invention. The alignment system and method in thisembodiment of the invention is based on the detection of theco-alignment of the first Purkinje reflection from the subject's eye 10with the center of the limbus 30 of the subject's eye. When the eye 10is appropriately illuminated by a light source, four Purkinjereflections can be detected but the first (anterior cornea) is thebrightest typically.

The elements of eye 10 necessary for understanding the present inventionwill be described briefly below. The cornea 12 of eye 10 ischaracterized by an anterior surface 16 and a posterior surface 14 thatare concentric with one another. The remaining portions of eye 10depicted in FIG. 1 are the iris 24 extending outward to posteriorsurface 14 of cornea 12. The circle of intersection between iris 24 andinterior surface 14 is an anatomical landmark known as the limbus, theposition indicated by reference numeral 26. The limbus 26 of an eye isvisible from the outside and is readily imageable.

In embodiments having aspects of the invention, a reference axis may bedefined by the co-alignment of the first, second, third, or fourthPurkinje reflection with the center of the limbus. The first Purkinjereflex is defined as the virtual image formed by the light reflectedfrom the anterior surface 16 of the cornea 12. The second Purkinjereflex is an image of the input light formed by the reflection from theposterior corneal surface 14. The light that is not reflected fromeither the anterior corneal surface 16 or the posterior corneal surface14 propagates through the cornea and aqueous humor, and through the lensof the eye onto the retina. The third Purkinje reflex is a virtual imageformed by the input light 14 reflected from the anterior surface of thelens, while the fourth Purkinje image is formed by light reflected fromthe posterior surface of the lens at its interface with the vitreoushumor. See, e.g., P. N. Cornsweet and H. D. Crane, J. Opt. Soc. Am., 63,921 (1973) for a more detailed discussion of Purkinje image formation,which is incorporated by reference.

Alternatively, the axis is defined by a Purkinje from an optionalsurface 34 placed over the eye 10 such as any of the eye contactsurfaces discussed in the priority applications incorporated byreference herein. Likewise, in FIG. 1, a reflection from cornealcovering 34 may be termed a “first Purkinje reflex”. See for example,the discussion below with respect to the embodiment shown in FIGS.5A-5B, in which the term “first Purkinje reflex” is used to describe areflection from an anterior surface of a device element (contact member520) which in operation is disposed over the corneal surface (this maybe a transparent member or may include a mirror surface to enhancereflection) and acts in certain respects as a surrogate for the anteriorcorneal surface 16.

In the embodiments described in particular detail, the geometricreference axis is identified and determined by the co-alignment of thecenter of the limbus 26 and a first Purkinje reflex. That is, thereference axis 18 in FIG. 1 is coincident with the center of the limbus26 and the plane 28 normal to the cornea 12 where plane 28 meets theanterior portion 16 of the cornea at point 32, which is substantially inthe center of the cornea of the eye. This reference axis is, oraccurately approximates and represents, the geometric axis of the eye,and therefore, the term “geometric axis” may be used interchangeablywith “reference axis” in this example.

FIG. 1 shows a block diagram of a system 100 for carrying out a methodhaving aspects of the invention. In the illustrated embodiment, system100 includes a camera 102 positioned to image eye 10 along the geometricaxis 18. Camera 102 provides video image data of eye 10 on a display104. Coupled to display 104 is an image generator 106, such as apersonal computer programmed with commercially-available computer aideddesign software, capable of generating and overlaying geometric imagesonto the image of eye 10 appearing on display 104. In operation, imagegenerator 106 overlays an image on the image of eye 10 on display 104.The overlaid image is typically a geometric shape sized and positionedto coincide with an anatomical landmark appearing in the image of eye10. The selected anatomical landmark should be one that remainsunchanged in size, shape and position relative to the eye 10.

A preferred anatomical landmark is limbus 26, which is generallycircular. Accordingly, as a first step, image generator 106 can beoperated to position an image of a circle on the image of limbus 26.Image generator 106 comprises a processor and can locate the center 30of limbus 26 using the processor within the system. Next, the firstPurkinje reflex 32 is identified. Light from light source 108 travelsalong path 35, entering the eye 10 through the cornea 12 and is directedby the lens to the retina. A portion of the light is reflected at point32 off the anterior surface of the cornea 16 (or optionally, theanterior surface of the covering 34), identifying the first Purkinjereflex. Alignment of the limbus center 30 with the first Purkinje reflex32 defines and allows accurate location of the geometric axis 18. Thegeneration of these image coordinates is well understood in the fieldsof computer graphics and computer aided design. Thus, one embodiment ofthe invention includes an image capture system 102 for generating analignment along the geometric axis 18 from information captured at twodistinct but interrelated locations in a subject's eye 10. In apreferred embodiment, the alignment is generated from a combined imageof the limbic center 30 and the corneal reflex at location 32.Alternatively, in another embodiment, covering surface 34 provides areflective surface for a Purkinje image 38.

The limbic center 30 and the anterior corneal Purkinje reflex 32 areocular features that are both independent and strongly coupled. They areindependent in that they are extracted from different biologicalstructures; they are strongly coupled because there is generally a closegeometric relationship between the limbic center 30 and the anteriorcorneal reflex 32 which is derived from the apex of the curvature of thecornea. Specifically, the position and orientation of the eye can bedetermined simultaneously when these two ocular features are co-aligned.The strong coupling between the limbic center and the anterior cornealreflex ocular features not only facilitates the simultaneous capture ofboth, but allows these features to be cross-referenced or combined in acommon feature space that preserves the geometric relationship betweenthe two.

As noted above, an image capture system 102 generates images 106 ofthese features by capturing an image of the anterior corneal reflex,capturing an image of the limbic boundary, processing these images, andcorrelating the spatial distribution of the limbic center and theanterior corneal reflex to provide a combined limbic center/Purkinjereflex image, or covering lens center/Purkinje reflex center. The imagecapture system 102 includes, or is attached to, one or more lightsources 108 such as LED(s) that direct light to the surface of eye 10.The camera system 102 preferably includes optics which include at leastone partially reflective mirror that directs light to the eye 10 andthat passes light reflected from the eye 10 to an image capture device102. The optics also include, in one embodiment, a lens system with oneor more lenses such that light from the light source 108 is directed toreflect from the anterior corneal surface 32 wherein the light reflectedfrom the anterior corneal surface 32 represents a first Purkinje reflex.The lens system also directs light from the light source 108 to reflectthe light from the iris 24, the light reflected from the outer irisrepresenting the limbic boundary.

In one embodiment, the light reflected by the anterior cornea at point32 and the light reflected by the iris 24 are simultaneously captured byan image capture device 102, such as a digital image capture device, anddisplayed on display 104 so as to capture and generate a combined imageof a limbic boundary and a first Purkinje reflex that can be used todetermine ocular alignment. In one embodiment, the image capture device102 is formed of two cameras that respectively capture an image of afirst Purkinje reflex 32 and an image of an iris 24 and sclera 17 whichdetermines the limbic boundary at the same time or near in time. In thisembodiment, a limbic boundary representing at least a portion of thecaptured iris and a first Purkinje reflex representing at least aportion of the anterior corneal reflex are generated wherein the limbiccenter and the first Purkinje reflex are correlated. These correlatedimages can be combined together to form one image or they can be linkedso that they can be analyzed as either one image or as two separateimages. In the various embodiments of the present invention, thecombined limbic center and first Purkinje reflex information provides aunique axis geometric axis 18 that can be used to determine eyealignment, treatment and/or diagnostic references.

Objective eye alignment can be determined by positioning the subject'seye 10 relative to the image capture device 102 to allow imaging of thesubject's eye. The image capture device obtains data on the patient'seye while the subject's face is placed approximately upright on andsecured by an articulated head restraint such that the subject's eyesface substantially forward, in the direction of the image capture device102. In certain embodiments, the image capture device is adjustable,e.g., using a joystick. The joystick can be tilted horizontally,vertically, or both horizontally and vertically, on a fixed base, inorder to adjust the location and/or image displayed on the display 104by the imaging module 400.

A light beam 35 is applied to the subject's eye 10. The image capturedevice 102 detects a portion of the beam 35 returned after striking thesubject's eye 10 and generates, based on the detected portion of thebeam, a limbus image of a limbus portion of the subject's eye and/or afirst Purkinje reflex of the subjects eye, which can be displayed ondisplay 104. By observing positions of the limbus image and the firstPurkinje reflex, objective and reproducible eye alignment can bedetermined. A concentric co-alignment of the first Purkinje reflex ofthe subject's eye and the center of the limbus of the subject's eyeestablishes the alignment of an ocular geometric axis 18 with the system100.

In some embodiments of the invention, the system 100 further includes acontroller to control the time at which the image capturing device 102respectively captures images of the cornea and limbus and couplesdigital representations thereof to the controller for analysis. Thecontroller preferably includes a microprocessor and associated memory.The microprocessor may analyze the captured cornea and limbus images togenerate a respective first Purkinje reflex and a limbus center whichare combined or linked together as described below. Alternatively, themicroprocessor may store the captured and correlated images fortransmission via a communication interface to a remote computer foranalysis and to generate the respective limbus center, first Purkinjereflex and combined or linked ocular information. In this embodiment,before transmitting data representing the captured images, themicroprocessor determines whether the captured images are sufficient toprovide alignment data, i.e. data used to align the eye. If the cornealreflex image is determined to be sufficient, the microprocessor controlsthe image capture device 102 to capture an image of the iris nearlysimultaneously with the captured corneal image that was determined to besufficient for providing eye alignment data. As used herein the termsimultaneously refers to being at the same time or near in time, e.g.,within approximately 0.5 seconds, such that the captured retina and irisimages are correlated.

Signal Generation Upon Optical Alignment

In one embodiment of the invention, the microprocessor controls one ormore of the cameras in the image capture device 102 to capture a cornealimage capturing and/or an iris image, and generate an alignment signalindicating that an eye is properly aligned with the system. Properalignment is when an axis intersects the eye at least two predeterminedfeatures on the eye, e.g., the limbus center and the first Purkinjereflex. The alignment signal may be generated by a switch or the likethat is manually actuated by a physician when the subject's eye isdetermined to be in alignment as displayed on display 104.Alternatively, the system can automatically detect when the eye is insufficient alignment with the system.

A signal is generated only when the beam path 35 of the light beamreflected from a measurement surface 32 is co-aligned with the center ofthe limbus 30 or center of covering surface 34. In order to achieveco-alignment, the image capture device 102, in cooperation with imagegenerator 106, recognizes the reflection of the probe beam 35 from theanterior corneal surface corresponding to the first Purkinje reflex, andthe center of the limbus. As shown in the graph 700 in FIG. 2, theco-alignment signal 710 is essentially zero until the coincidentreflection of the first Purkinje reflex and the center of the limbus aredetected 720. At point 730, the geometric axis is aligned with thesystem, and according to the invention, this signal can be used totrigger a subsequent desired event. Or indeed, at alignment, the signalis defined and then if there is a non-signal, this itself is a signalthat the device is out of alignment.

In one embodiment, an alignment signal activates an eyetracker apparatusfor monitoring the movement of the eye during a diagnostic ortherapeutic procedure or other desired function. In a conventionaleyetracker system, the patient may be asked to fixate on an illuminationsource while a visible laser beam coincident with a therapeutic beamaxis is directed onto the patient's cornea. Based upon the surgeon'sobservation of the visible laser beam in relation to the cornealposition, the surgeon will manually engage the eyetracker using his orher best judgment about the corneal position. Advantageously, accordingto the invention, the eyetracker can now be triggered automatically andmore accurately since the alignment signal will only be generated whenthe patient's geometric axis is properly aligned.

In certain embodiments, the eye-tracking system is configured to trackpatient movement, such as eye movement, for use by the system. Theeye-tracking system can calculate a three-dimensional image of thepatient's eye via physician inputs, and can include real-time trackingof movement of the patient's eye. The eye-tracking system obtains datathat becomes a factor for determining treatment planning for a number ofmedical conditions relating to the eye. For example, the eye-trackingsystem may create an image of the posterior region of the patient's eyeusing the data it obtains. In certain embodiments, the data can betransferred via cable communication or other means, such as wirelessmeans, to a treatment or diagnostic device. In certain embodiments, aprocessing module coupled to the treatment or diagnostic device mayprocess data on the patient's eye and present an image of the patient'seye on a coupled display. In certain embodiments, the coupled displaymay present a real-time image of the patient's eye, including movementof the eye.

In another embodiment, the alignment signal is utilized to reversiblyengage an ocular positioning and/or stabilizing device to the subject'seye, the ocular positioning and stabilizing device being in cooperativeengagement with the system. An exemplary positioning and/or stabilizingdevice is described in detail below, and illustrated in FIGS. 4A-5B.

Range Finder

In another embodiment of the invention, the system includes a proximitydetector (103 in FIG. 1) in the form of a range finder (camera) ortransducer such as an ultrasound transducer to determine when an eye isat a predetermined distance from the system. The proximity detector ispreferably positioned adjacent the image capture device 102. Theproximity detector is operated in a transmit and a receive mode. Thedistance between a system reference point (e.g., a selected pointco-linear with path 35) and the subject's eye (e.g., the corneal surface16) can be determined by the microprocessor or a dedicated integratedcircuit coupled to the proximity detector. The microprocessor orintegrated circuit calculates the distance between the eye and thesystem to determine the proximity of the eye to the system.

In one embodiment, the microprocessor or integrated circuit compares thedetermined distance between the eye and the system to a predetermineddistance value stored in the memory, a register or the like, accessibleby the microprocessor or integrated circuit. When the microprocessordetermines from the output of the proximity detector that the individualis at a predetermined or correct distance, the microprocessor signalsthe image capture device 102 to capture an image of an area of thelimbus 26. Simultaneously, the microprocessor may signal the imagecapture device 102 to capture an image of the cornea 12. In oneembodiment, the microprocessor first controls the image capture device102 to capture an image of the cornea which is immediately analyzed bythe microprocessor to determine whether the first Purkinje reflexcaptured is sufficient to provide alignment information as discussedabove. When a sufficient first Purkinje image is detected, themicroprocessor signals the image capture device 102 to capture an imageof the limbus 26. In this embodiment, the microprocessor analyzes thecaptured image of the cornea for sufficiency in sufficient time that themicroprocessor can signal the image capture device to capture an imageof the limbus near enough in time to the captured image of the cornea sothat the images are correlated and can be considered simultaneouslycaptured.

Note, that in addition to use in operation of the alignment system asdescribed above, the proximity detector can be configured to monitor eyedistance over any selected time period, for example after the alignmentof the eye reference axis (e.g., axis 18) by the alignment system,during treatment or diagnostic operation (e.g., input for controlsfeedback, safety interlocks and the like).

Coupling the Alignment System to a Treatment System

In some embodiments of the invention, the system alignment is directly,or indirectly, coupled to a treatment or diagnostic device. Thealignment method is used in combination with a treatment device to treata wide variety of medical conditions relating to the eye. As discussedin further detail below, once the reference axis is defined, it can begeometrically linked to anatomic structures of the eye which may be ofinterest in treating structures or diseases, e.g., tissue sites on theretina such as the macula affected by macular degeneration. Likewise,the reference axis may be linked to other regions of treatment of theeye, such as regions of the retina such as the fovea, the macula, apathologic lesion such as a tumor, a growth of blood vessels, amembrane, a telectasia, and an edematous region, and the like.

For example, the system may be used alone or in combination with othertreatments to treat macular degeneration, diabetic retinopathy,inflammatory retinopathies, infectious retinopathies, tumors in, around,or near the eye, glaucoma, refractive disorders, cataracts,post-surgical inflammation of any of the structures of the eye (e.g.,trabeculoplasty, trabeculectomy, intraocular lenses, glaucoma drainagetubes, corneal transplants, infections, idiopathic inflammatorydisorders, etc.), ptyrigium, dry eye, and other ocular diseases or othermedical conditions relating to the eye. The treatment system ispreferably a radiotherapy system that also includes controls fordefining the maximum beam energy (e.g., ranging between about 30 keV toabout 150 keV), beam angles, eye geometries, and controls to turn offthe device when the patient and/or eye move out of position.

The radiotherapy treatment system includes, in some embodiments, aradiation source, a system to control and move the source to acoordinate in three-dimensional space, an imaging system, and aninterface for a health care professional to input treatment parameters.Specifically, some embodiments of the radiotherapy system include aradiotherapy generation module or subsystem that includes the radiationsource and the power supplies to operate the source, an electromotivecontrol module or subsystem that operates to control power to the sourceas well as the directionality of the source, a coupling module thatlinks the source and control to the eye, and an imaging subsystem. Insome embodiments, these modules are linked to an interface for ahealthcare professional and form the underpinnings of the treatmentplanning system. In another embodiment described below, the treatmentsystem is a photoablative laser surgery system.

FIGS. 3A and 3B illustrate two examples of embodiments having aspects ofthe invention, in which the alignment system is coupled to a treatmentsystem (e.g., a radiotherapy device, an ablation laser, or the like) andconfigured to provide operative control and/or monitoring of thetreatment system functionality, such as position control, orientationcontrol, timing control, power enablement-disablement, and the like. Inthe examples shown, the alignment system is coupled to a treatmentsystem, where image generator 306 is coupled to a positioning device 310used to position an ophthalmic treatment device (312 and 314 in FIGS. 3Aand 3B, respectively), e.g., an ablation laser or radiotherapy device.

In FIG. 3A, the position of the geometric axis 18, properly located bythe alignment system, can be used by positioning device 310 to directophthalmic treatment device 312 at a tissue target 318, which may or maynot be positioned along axis 18. In this example, target 318 ispositioned off-axis with respect to geometric axis 18, as furtherdiscussed below.

In FIG. 3B, the position of the geometric axis 18, properly located bythe alignment system, can be used by positioning device 310 to “center”ophthalmic treatment device 314 on the eye's geometric axis 18, forexample, where as a treatment target is centered on the geometric axis,as further discussed below.

In these embodiments of the invention, the position of the eye and thetreatment device are known at all times, and the angles of entry of thetherapeutic or diagnostic beam can therefore be realized. For example,the geometric axis of the eye can be determined and defined as thereference axis of the system. A treatment axis may be defined withrespect to the reference axis, and then the treatment device may bepositioned at a known angle and/or offset distance from the referenceaxis. For treatment targets lying on the reference axis, the treatmentaxis may be defined as the reference axis. Depending on the region to betreated, the treatment device can be readjusted; for example, a robotarm can move the treatment device to a position to send a therapeuticbeam to a location on or in the eye.

Returning to the embodiment illustrated in FIG. 3A a schematic view isshown of an alignment and treatment embodiment, including across-sectional view of a portion of the eye taken along the geometricaxis. System 300 includes an image capture device 302 positioned toimage eye 10 along the geometric axis 18. Image capture device 302provides video image data of eye 10 to a display 304. Coupled to display304 is an image generator 306, such as a personal computer programmedwith commercially-available computer aided design software, capable ofgenerating and overlaying geometric images onto the image of eye 10appearing on display 304. In operation, image generator 106 overlays animage on the image of eye 10 on display 304. The overlaid image istypically a geometric shape sized and positioned to coincide with ananatomical landmark appearing in the image of eye 10. The selectedanatomical landmark should be one that remains unchanged in size, shapeand position relative to the eye 10.

A preferred anatomical landmark is limbus 26, which is circular.Accordingly, as a first step, image generator 306 can be operated toposition an image of a circle on the image of limbus 26. Image generator306 can then locate the center 30 of limbus 26. Next, the first Purkinjereflex 32 is identified. Light from light source 308 travels along path35, entering the eye 10 through the cornea 12 and is directed by thelens to the retina. A portion of the light is reflected at point 32 offthe anterior surface of the cornea 16, identifying the first Purkinjereflex. Alignment of the limbus center 30 with the first Purkinje reflex32 defines and allows accurate location of the geometric axis 18 as areference axis with respect to the external coordinate system.

With the position of the geometric axis 18 properly located, thegeometric axis 18 becomes an axis of reference, and can thereby be usedby positioning device 310 to direct ophthalmic treatment device 312toward the eye at a predetermined orientation with respect to fromgeometric axis 18 such that a therapeutic beam, such as a beam ofcollimated electromagnetic radiation 311, can be aimed at apredetermined coordinate of the eye 10 so as to enter the body surface(point 324 on the surface sclera 17) and propagate to impinge on aselected target tissue 318.

Note that FIG. 3A is a planar illustration of 3-dimensional eye anatomy,and in general beam axis 311 of device 312 need not intersect thegeometric reference axis 18 (i.e., axes 18 and 311 may, but need not,lie within a plane). In general, the beam axis 311 may have a selectedorientation with respect to geometric reference axis 18, such as aselected angle “θ” and offset “d” with respect to axis 18. The device312 can in fact be angled to intersect any anterior-posterior linewithin the eye.

Once reference axis 18 is identified, treatment may be carried out by adevice oriented with respect axis 18, for example where a treatmenttarget lies along axis 18 (see description regarding FIG. 3B).Alternatively, a distinct axis 19 may be defined with respect to axis18, for example by a shift of distance “d”, so that axis 19 intersectstreatment target 318 positioned off-axis with respect to axis 18. Axis19 may be called the “treatment” axis. Based on straightforwardgeometry, the device 312 can now be positioned so that its beam axis 311intersects treatment axis 19 at tissue target 318. Axis 18 may be usedto define one or more correlated geometric axes in the externalcoordinate system, and to define one or more additional intersectionpoints with respect to beam 311. Note for treatment targets lying onreference axis 18, offset “d” may be about zero, and for treatmentdelivered through or to the cornea, angle “θ” may approach zero.

FIGS. 3C-3D illustrate an example of an embodiment in which thealignment system is coupled to a treatment system adapted fororthovoltage X-ray treatment of a region of the retina generallyincluding the macula. FIG. 3C a cross-sectional view of an eye takenalong the geometric axis in a horizontal plane, shown in associationwith alignment-treatment system 300. FIG. 3D is a detail frontal view ofan eye as seen aligned with axis 18 (temporal to right, nasal to left).

As shown in FIG. 3D, although a single beam axis 311 may be employed, aplurality of beam axes may be defined in which two or more treatmentbeams are aimed to impinge on target 318 stereotactically. Treatmentaxis 19 may be chosen to intersect a selected target 318 within the eye,and employed as a reference to orient two or more treatment beams aimedto impinge on target 318 stereotactically. In the example of FIG. 3D,treatment axis 19 is chosen to intersect a selected target 318 withinthe eye, and employed as a reference to orient three treatment beamsprojected along three different beam axes 311 a, 311 b and 311 c, thebeam axes defined so as to each impinges on target 318 from a differentdirection.

Multiple beams may be projected simultaneously, or sequentially, withintervening periods of no treatment if desired. Likewise, multiple beamsmay be provided by multiple separately-positioned treatment devices.However, a preferred embodiment employs a single treatment device 312(e.g. a collimated orthovoltage X-ray source), which is sequentiallyrepositioned by positioning device 310 to administer treatment insequential doses along each of a plurality of beam axes, such as axes311 a, 311 b and 311 c.

The beam axes each have a different respective point of entry into thebody surface (324 a, 324 b and 324 c respectively) and each follows adifferent tissue path leading to target 318. Likewise each beam followsa different tissue path for any propagation beyond target 318. In thisway, treatment beam dosage penetrating tissue remote from target 318 maybe minimized relative to the dosage received at target 318.

Beam axis 311 (or for multiple beams, each of axes 311 a-c) may beselected to follow a tissue path which avoid vulnerable structures ortissues which are remote from target 318, so as to minimize dosagereceived by such tissues. For example, in treatment of the macula formacular degeneration, axes 311 a-c may be selected to deliver a selecteddose of beam treatment (e.g., a selected dosage of absorbed X-rayenergy) to a target 318 on or near the retina 340, centered on themacula 342 while minimizing absorbed radiation by the optic nerve 350,the lens, and the like.

In the example shown, three beam axis 311 a, 311 b and 311 c aredefined, so that the beams directed towards the posterior eye enter thebody on the surface of the anterior sclera 17 at points 324 a, 324 b and324 c, each entry point a selected distance beyond the limbus 26. Suchbeam orientation can avoid or minimize absorption by the lens and otherstructures within the eye, by appropriate selection of the beam paths.

Positioning device 310 may provide for robotic control with any selecteddegrees of freedom and may have corresponding feedback sensors to permitaccurate treatment control by a processor and/or manual operator. Seefor example, high degree-of-freedom robotic surgical control systemssuch as employed in the CyberKnife® robotic radiosurgery system(Accuray, Inc. Sunnyvale, Calif.) and the da Vinci® minimally-invasivesurgical system (Intuitive Surgical, Inc., Sunnyvale, Calif.). Suchsystems can provide for a high degree of operational range andflexibility. Note that in the most general case, treatment axis 19 neednot be parallel to reference axis 18, and target 318 may be locatedrelative to axis 18 by other analytical methods not including aseparately-defined treatment axis. On the other hand, a real or at leastconceptual hazard of high degree-of-freedom robotic systems employingenergy beam treatment, is the large possible range of beam paths (e.g.,upon a control system failure), and associated risk issues, regulatorycomplexity, and high end-user installation and site modification costs.

Important safety and regulatory/validation advantages, and well ascompactness and cost reduction, may be provided by configuringpositioning device 310 to have a reduced degrees of freedom andsimplified control devices and/or software. Particularly where atreatment system is optimized for a particular range of treatmentprocedures (e.g., treatment targets in or near the retina), a finitenumber of rotational or translational degrees of freedom (e.g., track orpivot mounted electrical actuators) can provide the desired range ofselectable beam paths to administer a medically optimal dosage to thetreatment target.

As illustrated in FIG. 3D, one or more of beam axes (311 a, 311 b and311 c) are defined such that each axis lies within a conical conceptualsurface and whereby each beam intersects the apex of the cone. The conemay be defined having as its conical axis the treatment axis 19 with theapex disposed at target 318. In this example, treatment axis 19 isdefined parallel to reference axis 18, having x-y offsets define in anperpendicular plane by “dx” and “dy” respectively (for a treatmenttarget intersected by the reference axis the offsets are zero). Once thetreatment axis 19 is defined, the base 34, the apex angle (“θ” in FIG.3C), and rotational positions of axes 311 a-c with respect to axis 19,may be adjusted to provide both beam intersection at about target 318 aswell as to provide entry points 324 a-c located at a desired position ofthe body surface.

As shown in FIG. 3C, in one example of an orthovoltage X-ray treatmentfor macular degeneration, off-sets dx and dy are selected to define atreatment axis 19 centered on the macula, angle θ is selected to provideintersection of beams 311 a-c on the macular surface, and base 34 isselected to provide surface entry points 324 a-c in a region of thelower anterior sclera beyond the boundary of limbus 26. In this example,an X-ray beam source may positioned by positioning device 310 so as toproject a collimated beam from a selected X-ray source distance so as toform a beam having a characteristic width at tissue entry “w”. Note thatalthough a treatment beam may be projected through an eye-lid or othertissue proximal to the eye, the eyelids (in this case the lower eyelid)may be conveniently retracted so as to expose an additional area of theanterior sclera 17.

In the example shown in FIGS. 3C-3D, target 318 is approximately thefovea 344. As shown in FIG. 3C, collimated orthovoltage X-ray beam 311at entry to the sclera has a effective beam with of W_(e) (e.g., asdefined by a boundary at the 90% isodose). The beam 311 spreads at itpropagates through the eye, to have an effective beam width of W_(t),which covers an area surrounding the target constituting the treatmentregion, in this case corresponding to the macula.

In the example shown, for each beam axis 311 a-c, a rotational angle

may be selected to define a distinct propagation path for the beam(e.g., a path which avoids vulnerable structures such as the optic nerve350 and which is sufficiently distinct from other treatment beams toreduce collateral tissue dosage). Note that where the treatment axis 19is offset from geometric reference axis 18, the points 324 a-c will tendto be different distances from limbus 26, and the combination off base34 and rotational angle

for the closest beam may be selected to assure a desired minimum cornealclearance “c” for beam entry (324 a in FIG. 3B).

The positioning device 310 may conveniently have actuators providing for5 degrees of freedom of motion for treatment device 312, such asproviding x-y-z adjustment relative to the patient's eye, and rotationfor the angles θ and

to direct each of beams 311 a-c to target 318 along a distinct path.See, for example the constrained positioning system for an X-ray sourceand collimator, as described and shown with respect to FIGS. 12E-F ofco-invented/owned U.S. patent application Ser. No. 12/100,398, entitled“Orthovoltage Radiosurgery” filed Apr. 9, 2008 by Gertner et al., whichis incorporated by reference.

Without departing from the spirit of the invention, one of ordinaryskill in the art will appreciate that for a specialized device optimizedfor a particular range of treatments, fewer degrees of freedom may beprovided, as, for example, when certain of the parameters described mayreasonably be fixed. Note in this regard that an eye positioning and/orstabilizing device, such as shown if FIGS. 4-5, may include actuators(or employ manual patient movement) sufficient to change the positionand orientation of the treated eye 10, so as to substitute for degreesof freedom of the positioning device 310 with respect to the treatmentdevice 312. Thus, the patient and/or eye may be moved in one or moreparameter with respect to device 312, until it is determined that thetreatment path 311 is correctly aimed at target 318 (which may beconfirmed by the alignment system).

In some embodiments, one or more additional imaging camera systems maybe included. In the example shown in FIG. 3A, camera 322 is configuredto be positioned by positioning device 310, and aimed so as to obtain animage of the area of intersection of therapeutic beam 311 with anexposed body surface, such as an exposed area of the scleral surface ofthe eye. Additionally, a reference light beam may be provided toilluminate and/or mark the of intersection area. For example, device 312may incorporate a laser pointer beacon along a path coincident withtherapeutic beam 311 (e.g., directed by a co-aligned mirror), so as toindicate the intersection of beam 311 on a surface of the eye (e.g., forvisual or automated confirmation of the alignment of beam 311, or thelike). Alternatively, a reference light beam may be provided which isnot aimed along a path coincident with therapeutic beam 311, forexample, configured to be aimed by positioning device 310 on a pathintersecting the surface at area (see FIG. 2C and related description ofco-owned U.S. application Ser. No. 11/873,386 filed Oct. 16, 2007, whichis incorporated by reference).

In the embodiment depicted in FIG. 3B, system 350 includes a camera 302positioned to image eye 10 along the geometric or reference axis 18.Camera 302 provides video image data of eye 10 to a display 304. Coupledto display 304 is an image generator 306, such as a personal computerprogrammed with commercially-available computer aided design software,capable of generating and overlaying geometric images onto the image ofeye 10 appearing on display 304. In operation, image generator 306overlays an image on the image of eye 10 on display 304. The overlaidimage is typically a geometric shape sized and positioned to coincidewith an anatomical landmark appearing in the image of eye 10. Theselected anatomical landmark should be one that remains unchanged insize, shape and position relative to the eye 10.

A preferred anatomical landmark is limbus 26, which is circular.Accordingly, as a first step, image generator 306 can be operated toposition an image of a circle on the image of limbus 26. Image generator306 can then locate the center 30 of limbus 26. Next, the first Purkinjereflex 32 is identified. Light from light source 308 travels along path35, entering the eye 10 through the cornea 12 and is directed by thelens to the retina. A portion of the light is reflected at point 32 offthe anterior surface of the cornea 16, identifying the first Purkinjereflex. Alignment of the limbus center 30 with the first Purkinje reflex32 defines and allows accurate location of the geometric axis 18. Withthe position of the geometric axis 18 properly located, the geometricaxis 18 becomes an axis of reference, and can thereby be used bypositioning device 310 to direct ophthalmic treatment device 314 towardthe eye and co-aligned with the geometric axis 18 such that atherapeutic beam, such as a beam of an ablation laser 316, can be aimedat a predetermined coordinate of the eye 10, such as point 32 on thecornea 12 of eye 10.

The treatment device 314, in one embodiment of the invention, is autilized for treating macular degeneration of the eye usingradiotherapy. For example, in some embodiments, systems and methods aredescribed for use of radiotherapy on select portions of the retina toimpede or reduce neovascularization of the retina. Some embodimentsdescribed herein also relate to systems and methods for treatingglaucoma or controlling wound healing using radiotherapy. For example,embodiments of systems and methods are described for use of radiotherapyon tissue in the anterior chamber following glaucoma surgery, such astrabeculoplasty, trabeculotomy, canaloplasty, and laser iridotomy, toreduce the likelihood of postoperative complications. In otherembodiments, systems and methods are described to use radiotherapy totreat drusen, inflammatory deposits in the retina that are thought tolead to vision loss in macular degeneration. Localized treatment ofdrusen and the surrounding inflammation may prevent the progression ofdry and/or wet AMD.

In some embodiments, laser therapy is applied to drusen in combination(adjuvant therapy) with co-localized x-ray radiation to substantiallythe same location where the laser is incident upon the retina; the lasercan create a localized heating effect which can facilitate radiationtreatment, or the laser can ablate a region, or laser spot, while theradiation can prevent further scarring around the region. Suchcombination therapy can enhance the efficacy of each therapyindividually. Similarly, adjuvant therapies can include x-rayradiotherapy in combination with one or more pharmaceuticals or otherradiotherapy-enhancing drugs or chemical entities. In some embodiments,x-ray therapy is combined with invasive surgery such as a vitrectomy,cataract removal, trabeculoplasty, trabeculectomy, laserphotocoagulation, and other surgeries.

Reversibly Coupling an Ocular Device to the Eye Following Alignment

Referring now to FIGS. 4A-4B, following identification of the geometricaxis 18, as described in detail above, an ocular device, e.g., theocular device 400 described in co-owned U.S. provisional application No.61/020,655, filed Jan. 11, 2008, entitled, “System and Method forPositioning and Stabilizing an Eye,” which is incorporated by referenceherein, can be positioned onto, and aligned with eye 10. Followingpositioning and alignment, the ocular device 400 can be utilized for anumber of methods, including

-   -   (i) controllably stabilizing the eye,    -   (ii) physically manipulating the eye position,    -   (iii) limiting eye movement during treatment,    -   (iv) providing a positional reference relative to external        coordinates of the surface of the eye and its internal anatomy,    -   (v) providing fiducials relative to the eye,    -   (vi) maintaining corneal lubrication during treatment, and    -   (vii) providing a mechanism to align a treatment device and        continuously signal indicative of adequate alignment or        misalignment.

FIGS. 4A-4B schematically illustrates a top-down view of the oculardevice 400 being reversibly and controllably coupled to the cornea 12and/or limbus 24 of the eye 10, in association with alignment system100. Note that ocular device 400 (and other ocular device embodimentshaving aspects of the invention) may be usefully employed independentlyfrom alignment systems, such as system 100. The ocular device may besupported by a mounting (not shown) coupled to positioning arm 480 so asto maintain the eye in a first position to provide stability for the eyewhile the eye is being treated. The mounting may be configured tomanually and/or robotically adjust the position of device 400 and eye10. The ocular device 400 includes a contact member 420 which contactseye 10. The contact member 420 can be positioned on the eye in a varietyof positions, and is therefore useful in a wide variety of oculartreatment procedures. As further illustrated in FIG. 4B, the eye contactmember 420 includes a curved structure that is generally centered on theaxis 18 and contacts portions of the anterior surface of eye 10. As willbe seen below with reference to FIG. 5A, the ocular guide may provide anouter reflecting surface normal to and intersected by the center axis ofthe eye contact member, allowing eye alignment by using a reflectionfrom this reflecting surface as a Purkinje reflection, that is, as asurrogate for the first Purkinje reflection off the anterior surface ofthe cornea.

In some embodiments, the contact member 420 contacts all or a portion ofthe corneal surface 16, and in some embodiments, the contact member 420contacts portions of the surface of the sclera 17 (represented by dashedlines) disposed adjacent the limbus 26 while cover all or a portion ofthe corneal surface 16. For example, in one embodiment, the eye contactmember 420 has a profile configured so that the periphery 437 of thecontact member 420 is in contact with the sclera 17 adjacent the limbus26, and configured so the center portion of the contact member 420substantially cover the cornea, but is not in direct physical contactwith at least a central portion of the cornea.

In another alternative embodiment, contact member 420 may be sized andconfigured so that in operation, it covers a majority of the cornealsurface, while leaving all or a portion of the limbus 26 visible beyondthe edge 437 of contact member 420. In this embodiment, a camera of analignment system (see, for example, FIGS. 1 and 6) may be arranged toobtain and may process images of the limbus while contact member 420 isin contact with the cornea 12. For example, a camera, such as camera 102or another camera may be provided, configured to enable an alignmentsystem to confirm the placement and stability of contact member 420 bythe spatial relationship of member 420 to limbus 26.

The eye contact member 420 may be held against eye 10 by a selected biasforce, e.g., as applied mechanically via positioning arm 480. Inaddition, or alternatively, vacuum suction may by employed to createattraction between member 420 and the surface of eye 10. The eye holderillustrated in FIGS. 4A-4B includes a vacuum port 410 which functions asan air and/or fluid passage and can be adapted for coupling to a vacuumsource through vacuum line 275. In the embodiment illustrated in FIGS.4A-4B, the vacuum port 410 is positioned through the eye contact member420 such that an air or fluid communication space is formed through eyecontact member 420 to allow air trapped between eye contact member 420and the anterior surface of the cornea 12 of eye 10 to be removed,thereby reversibly engaging the eye contact member 420 with the anteriorsurface of the eye in the region of the cornea 12. Vacuum pressure maybe adjusted for patient comfort, and in relation to bias force and cupgeometry. For example, a vacuum pressure of about 25 mm Hg or less hasbeen shown to be adequate to provide eye stability in one embodimenthaving aspects of the invention. When the ocular device is seated ontoand coupled with eye 10, the mirror 430 is aligned such that it issubstantially parallel to plane 28 (normal to the cornea 12 at axis 18coincident with the center of the limbus 26). In this way, the mirror430 becomes an additional alignment tool for performing an alignmentprocedure on a subject's eye 10. Alignment methods having aspects of theinvention may include identifying a reflection of beam 35 (light source108) from mirror 430, and aligning the refection with respect to ananatomical landmark, such as the center of limbus 26. Such methods maybe employed in addition to or instead of alignment methods based on afirst Purkinje reflex from the surface 16 of cornea 12 as describedabove with respect to FIG. 1.

Note that all or a portion of contact member 420 may comprise atransparent material, to permit an operator (and/or a system camera) tovisualize the relative position of eye structures such as the limbus 26as contact member 420 is brought into contact with eye 10, and whilemember 420 remains in contact.

An exemplary method for performing an alignment procedure following thepositioning of the ocular device 400 on the subject's eye 10 includessupporting the subject's head at a fixed position in an externalcoordinate system, determining the position and orientation of the eyeaccording to any of the methods described above, attaching to the frontof the eye 10 an ocular contact device 400 effective to stabilize theposition of the eye relative to the contact device 400, and thereafterdetermining the position and orientation of the ocular contact device inthe external coordinate system, thereby to determine the position andorientation of the patient's eye in the external coordinate system. Theeye 10 can thereafter be moved or positioned as desired, whilemaintaining stable contact between eye 10 and contact member 420, andwhile monitoring the motion or position of contact device 400 in theexternal coordinate system. For example, after attaching the eye 10 tothe ocular contact device 400, the method can include moving the ocularcontact device 400 to place the device 400 at a selected orientation inthe external coordinate system, such as by adjusting the angularposition of the contact member 420 with respect to the subject's head.The position of the ocular device in the external coordinate system withsuch placed in the selected orientation can then be determined.

In a related embodiment, with the ocular device 400 now positioned onthe eye, a therapeutic device can be utilized to provide therapeutictreatment to the subject's eye. In this embodiment, a source of acollimated electromagnetic beam, such as an x-ray beam, is positionedsuch that when it is activated, it is aimed along a selected line ofsight at a selected coordinate in the external coordinate systemcorresponding to a selected target region in the subject's eye.

FIGS. 17A-17D depicts embodiments of eyeholders 400 (a-d) having aspectsof the invention, similar in many respect to those shown in FIGS. 4A-Band FIGS. 16, having alternative configurations of contact member 420.For each figure, the eyeholder 400 is shown superimposed on a schematicfrontal view of a portion of an eye 10 having iris 24 adjoining regionof sclera 17, the junction of which defines limbus 26. For each figure,the eye 10 is shown aligned with reference axis 18 positioned at thecenter of limbus 26. In each figure, support post 422 is shown centeredon axis 420, although it need not be centered.

FIG. 17A depicts an embodiment in which contact member 420 is sized tohave a margin which may be positioned on the eye surface so as to leaveall or most of the limbus boundary 26 uncovered. This configurationfacilitates visual confirmation of placement of member 420. Thisconfiguration also facilitates the use of automated patternrecognition/boundary detection methods, for example, using imagescaptured by camera 102, or another camera disposed to capture images ofthe limbus. For example, proximity detector 103 in FIG. 1 may in certainembodiments include an optical rangefinder camera, which may also beemployed to determine the position of limbus 26 with respect to contactmember 420.

FIG. 17B depicts an embodiment in which contact member 420 is sized tocover all or a portion of limbus 26. In certain embodiments thecomparatively large contact or cup member 420 provides greater stabilityof eye control for a given combination of bias force and/or vacuumpressure, and may facilitate a contour which avoids direct contact withthe center of the cornea. Note that member 420 may comprise atransparent material permitting visualization of the covered portion oflimbus 26.

FIG. 17C depicts an embodiment in which contact member 420 is configuredto be asymmetrical with respect to limbus 26, and in operation may bepositioned off-center with respect to the limbic center (see axis 18).

FIG. 17D depicts an embodiment in which contact member 420 is configuredto include one or more lobes 440, the lobes extending beyond the limbus26, covering sclera regions adjacent one or more treatment beam entryregions 324. In the embodiment shown, the lobes surround portions of apattern of three radially arranged treatment beam entry regions similarto those shown in FIG. 3D. For example, in an eyeholder for use in anorthovoltage X-ray treatment system, the lobes may comprise a materialselected to absorb X-rays, e.g. to reduce dosage absorbed by the lens ofthe eye. In this example, a large portion of limbus 26 is exposed inportions of the eye surface not proximate to the treatment beams, andone or more fiducials 450 may be arranged to facilitate optical trackingdevices. In alternative embodiment (not shown) the lobes may completelysurround the beam entry regions 324.

FIG. 5A depicts a configuration of an eye holder 500, which is generallysimilar to eye holder 400 shown in FIGS. 4A-B, but in which the post 522is off-center from the central portion of the contact member-sclerallens cup 520. In particular, the offset from the center axis of theocular guide, indicated at 523, is sufficient to allow a light beamaimed along this axis to be reflected off the outer center region of theocular guide, unobstructed by a positioning arm 522 and a positioningarm 580. This allows outer surface of the ocular guide, normal to andintersecting axis 523, to provide a point of reflection for a beam aimedat the center of the eye, thus producing a Purkinje reflection thatcorresponds to the first Purkinje reflection from the anterior of thecornea, when the ocular guide is centered on the patient's eye. As inthe embodiments of FIGS. 4A-B, an optional vacuum source 575 is alsoprovided in this embodiment to provide suction engagement of cup 520with eye 10. All or a portion of contact member 520 may comprise atransparent material, e.g., a clear polymer such as PMMA (polymethylmethacrylate), to permit an operator to see the relative position of eyestructures such as the limbus 26 and iris 24 as contact member or cup520 is brought into contact with eye 10.

Additionally, transparency permits transmission of light into and backfrom the eye surface and interior through cup 520 while it is in contactwith eye 10, so as to enable observation internal eye structures throughthe cornea, such as the retina. Imaging camera 102 is also provided inthis embodiment. A feature of this embodiment is that the imaging camera102 can visualize an eye structure such as the fundus directly throughthe cup 520 while a therapy is being performed. A fundus image can beobtained through the clear portion of the scleral cup 520 without thepost in the way. The Purkinje of the contacting portion 520 and itscenter align to the Purkinje of the cornea and the alignment position523 of the contacting portion 520 can be used as a surrogate for whatwould be the alignment if the Purkinje of the cornea was used foralignment 18.

FIGS. 18A-18B depicts embodiments of eyeholders 500(a-b) having aspectsof the invention, similar in many respect to those shown in FIGS. 5A-Band 16, having alternative configurations of contact member 520. Foreach figure, the eyeholder 500 is shown superimposed on a schematic viewof a portion of an eye 10 having iris 24 adjoining region of sclera 17,the junction of which defines limbus 26. Each figure includes a frontalview (1) and a cross-sectional view (2) taken along line (2)-(2) in view(1).

FIG. 18A depicts an embodiment in which contact member 520 is configuredto include a window area 595 comprising a transparent material,permitting visualization of the eye interior through the central corneawhile eyeholder 500 a is in contact with the eye 10 (or the entirecontact member 520 may comprise a transparent material). The window 595may also be configured to facilitate visualization or capture of animage to the reflection of a collimated or coherent light beam from theouter surface of window 595, as describe in the alignment methodsherein. Vacuum port 510 is configured to apply a suction force adheringeyeholder 500 a to eye 10. Note that any space between window 595 andthe corneal outer upper surface 16 may be filled with an ophthalmicsolution or gel, which may be composed to reduce refractive effectsbetween window 595 and the cornea. Support post 522 may be arranged tomount to contact member 520 off-center with respect to window 595, so asnot to obstruct visualization through the window. In this example,contact member 520 is sized-shaped to leave all or a greater portion oflimbus 26 uncovered.

FIG. 18B depicts an embodiment in which eyeholder 500 b is configured ina generally similar arrangement to eyeholder 500 a of FIG. 18A, but inwhich a central opening 597 is provided so that the central corneasurface 16 is exposed. Contact member 520 is configured in an annularring shape which surrounds all or a portion of the boundary opening 597.Alternatively, member 520 may be not be entirely closed about theperiphery of opening 597, for example having a “C” shaped planformrather than an “O” shaped planform. In the example shown, an annulargrove 512 is recessed into the under surface (eye-contact surface) ofmember 520, to facilitate the distribution of vacuum pressure formcommunicating vacuum port 510 around the peripheral contact area ofmember 520. The embodiment shown permits a first Purkinje reflection tobe conveniently captured or visualized from the outer corneal surface 16while eyeholder 500 b is in operative contact with eye 10, facilitatingembodiments of the alignment methods described herein.

FIGS. 16A through 16B depict alternative species having aspects of theinvention of a “breakaway” post fitting which may be employed with eyepositioning and/or stabilizing devices such as shown in FIGS. 4A-B and5A-B. It is advantageous to have a eye stabilization device 400 as shownin FIGS. 4A-B (or 500 as in FIGS. 5A-B) in which the eye contact memberor cup 420 (520) can remain coupled to the eye 10 in the event that apatient voluntarily or involuntarily pulls away from the alignmentsystem 100 after the contact member is coupled to the eye, or if theoperator determines to disengage positioning arm 480 (580) at some pointin a patient procedure. For example, a patient may sneeze or becomestartled during the course of a procedure, causing the patient to moveinvoluntarily.

Each of FIGS. 16A through 16F depicts a portion of an eyepositioning/stabilizing system 400 (500) eye contact member 420 (520)mounted to a multi-part post 422 (522), comprising a proximal postportion 422 a (522 a) coupled to the contact member and a distal postportion 422 b (522 b) coupled to the eye stabilization device, the postproximal and distal portions being configured to releasably engage oneanother. Each of FIGS. 16A-16F includes matched pair of views, in whichview (1) shows the proximal and distal portions 422 a-422 b engaged, andview (2) shows the proximal and distal portions 422 a-422 b disengagedin exploded view.

Each of the species of FIGS. 16A-16F may further include a vacuum lineand source as described above. In some embodiments, the vacuum line 475(575) may be mounted and connected so as to remain attached to the eyecontact member 420 when the post portions 422 a,b are disengaged. Forexample, in one embodiment, the vacuum line and source may be mounted toa patients clothing (such as a collar) so as to remain with the patient,should the patient move away from the overall system 100. Likewise, eachof the species of FIGS. 16A-16F may be employed with a bias forceapplied by the positioning arm (480 in FIGS. 4A-B) as described above.

It should be understood that the mechanisms illustrated in FIGS. 16A-16Fare exemplary, and variations will be apparent to one skilled in the artwithout departing from the spirit of the invention. For example, theconfigurations of post distal and proximal portions may generally bereversed. Likewise, the devices may include sensors configured to signalcontrol system processors upon engagement or disengagement of portions422 a,b.

FIG. 16A shows a device 400 in which the distal and proximal areprofiled to provide a socket 422 a and post 422 b in which theengagement only transmits significant compression force, but transmitslittle or no tensile force perpendicular the eye (e.g., is maintained inposition by bias force), while resisting lateral force. Thedistal-proximal portions may be permitted to swivel axially, or axialtorque may provide, if desired, by a keyed arrangement on the sides orbottom of the socket (not shown).

FIG. 16B shows a device 400 in which the distal and proximal portions422 a,b are generally similar to that of FIG. 16A, but in which thesocket and posts are profiled to provide a light “snap-bead” effectwherein one portion grips the other upon disengagement. Either or bothof portions 422 a,b may comprise an elastic material, and slots may beincorporated in either socket or post portions to increase flexibility.

FIG. 16C shows a device 400 in which the distal and proximal portions422 a, b include a magnetic coupling, for example where a permanent orelectro magnet and/or ferromagnetic material is incorporated into one orboth of portions 422 a,b, so as to create a pre-defined attraction forcebetween the engaged distal and proximal portions.

FIG. 16D shows a device 400 in which the distal and proximal portionsare generally similar to that of FIG. 16C, which additionally oralternatively includes an adhesive material which releasably bondsportions 422 a,b together, e.g., in the manner of adhesive tape or“post-it” products.

FIG. 16E shows a device 400 in which the distal and proximal portions422 a,b are generally similar to that of FIG. 16A, but in which thesocket and posts are deeply engaged so as to apply lateral force at aselected distance above the surface of the eye contact member.

FIG. 16F illustrates the adaptation of any one of the species of FIGS.16A-E to a “side-post” device 500, in which the post structure 522 a-522b is positions sufficiently off-axis so as to provide an unobstructedcenter portion 595, which may be transparent (a window for lighttransmission) to enable certain methods having aspects of the inventionas described herein.

Alignment by Limbus Sizing

In another embodiment of the invention, the alignment method utilizeslimbus sizing to define the geometric axis. In this embodiment, asillustrated in FIGS. 6A-C, a schematic side view of a portion of an eye10 is shown. The alignment system and method in this embodiment of theinvention is based on the detection of the maximal area of the limbus 26of the subject's eye 10. The cornea 12 of eye 10 is characterized by ananterior surface 16 and a posterior surface 14 that are concentric withone another, the iris 24 extending outward to posterior surface 14 ofcornea 12. The circle of intersection between iris 24 and interiorsurface 14 is an anatomical landmark known as the limbus 26. The limbusof an eye is readily imageable.

As discussed above, an “axis of interest” indentified as a referenceaxis for eye alignment method embodiments having aspects of theinvention may advantageously be, but is not necessarily, the opticalaxis or the geometric axis of the eye. The geometric axis 18 in FIGS.6A-C, may be determined to be aligned with the external coordinatesystem of system 100 when axis 18 is coincident with the center of thelimbus 26 when the area circumscribed by the boundary of the limbus ispositioned to achieve its maximum apparent area with respect to camera102. In the illustrated embodiment, camera 102 is positioned to imageeye 10 along direction 600. Light from light source 108 travels alongpath 35, entering the eye 10 through the cornea 12 and is directed bythe lens to the retina. Camera 102 provides video image data of eye 10to display 104. Coupled to display 104 is an image generator 106. Inoperation, image generator 106 generates an image of the limbus 26 anddisplays it on display 104. Accordingly, as a first step, imagegenerator 106 can be operated to generate a first image of limbus 26when the eye is in a first position, as shown in FIG. 6A. Imagegenerator 106 can then locate the boundary of limbus 26.

Next, the first area defined by the boundary of the limbus isdetermined. As shown, FIG. 6A depicts eye 10 angled such that the area610 defined by the boundary of the limbus is less than maximal. Thecamera 102, or preferably the eye 10, is then positioned in a secondposition and image generator 106 is operated to generate a second imageof limbus 26, as shown in FIG. 6B. Image generator 106 can then locatethe boundary of limbus 26. Next, the second area 611 defined by theboundary of the limbus is determined. As shown, FIG. 6B depicts eye 10angled such that the area 610 defined by the boundary of the limbus isless than maximal. This process is repeated until the maximum areadefined by the limbus boundary is identified, as illustrated in FIG. 6C,where direction 600 is co-aligned with the reference axis 18. Detectionof the maximum area 612 of limbus 26 signals the eye is in alignmentwith the system, and the reference axis 18 is defined.

Identification of the Limbic Boundary

As noted above, the limbic boundary is determined in the alignmentmethods described. Determination of the limbic boundary, and limbiccenter, can be accomplished in a variety of ways. An exemplary methodfor determining the center of the limbus is diagrammatically illustratedin FIG. 7, showing the sequence 700 of the successive data processingsteps to identify the limbic boundary and limbic center. Input image 710represents the relatively high-resolution eye image data that isapplied. The first data processing step 720 is to average and reduceinput image 710. This can be accomplished by convolving the datadefining input image 710 with a low-pass Gaussian filter that serves tospatially average and thereby reduce high frequency noise. Since spatialaveraging introduces redundancy in the spatial domain, the filteredimage is next sub-sampled without any additional loss of information.The sub-sampled image serves as the basis for subsequent processing withthe advantage that its smaller dimensions and lower resolution lead tofewer computational demands relative to the original, full size, inputimage 710.

The next data processing steps involved in localizing the limbusboundary, and center of the limbus, include the sequential location ofvarious components of the limbic boundary. In sequence, step 730 locatesthe limbic (or outer) boundary 732 of the iris. The localization stepcan be performed in two sub-steps. The first sub-step includes an edgedetection operation that is tuned to the expected configuration of highcontrast image locations. This tuning is based on generic properties ofthe boundary component of interest (e.g., orientation) as well as onspecific constrains that are provided by previously isolated boundarycomponents. The second sub-step includes a scheme where the detectededge pixels vote to instantiate particular values for a parameterizedmodel of the boundary component of interest.

In more detail, for the limbic boundary 732 of step 730, the image isfiltered with a gradient-based edge detector that is tuned inorientation so as to favor near verticality. Thus, even with occludingeyelids, the left and right portions of the limbus should be clearlyvisible and oriented near the vertical, when the head is in an uprightposition. The limbic boundary is modeled as a circle parameterized byits two center coordinates, xc and yc, and its radius, r. The detectededge pixels are thinned and then histogrammed into a three-dimensional(xc, yc, r)-space, according to permissible (xc, yc, r) values for agiven (x, y) image location. The (xc, yc, r) point with the maximalnumber of votes is taken to represent the limbic boundary. Finally, withthe limbic boundary 732 isolated, the final processing step 740 includeslocating the center 750 of the limbus.

The above-described approach to identifying the center of the limbus canbe generalized in a number of ways. For example, image representationsother than oriented gradient-based edge detection may be used forenhancing iris boundaries. Second, alternative parameterizations for theiris boundary may be employed. Finally, iris boundary localization maybe performed without the initial steps of spatial averaging andsubsampling.

Defining the Retinal Target Region Following Ocular Alignment

As described above with respect to FIGS. 1-5, a first Purkinje reflex(or an equivalent reflection from an corneal covering member, such aseye contact member 420 or 520) may be correlated and aligned relative tothe center of the limbus 26 to define a reference axis 18. The center ofthe limbus may be manually or automatically detected as described withrespect to FIGS. 6-7. Further the reference axis may be aligned with theexternal coordinate system of an eye positioning/stabilization systemand/or eye treatment.

One method embodiment having aspects of the invention includes aligningthe eye with the system coordinates and defining the reference axis, andidentifying a treatment target tissue region relative to theintersection of the reference axis with a portion of the eye, e.g., theretina. With the eye aligned as described above, and the reference axisdefined and correlated with an external coordinate system, a treatmenttarget tissue region within the eye can be identified and located withinthe external coordinate system.

In a further method embodiment having aspects of the invention includes,after a treatment target tissue is located with respect to the ocularreference axis as defined and aligned with respect to a treatmentsystem, the treatment device is positioned relative to this referenceaxis to deliver a desired treatment to the target tissue (e.g., aretinal target region at or near the macula).

FIG. 8A depicts a cross-section of a subject's eye 10 in a saggital(Z-Y) axis to include an anterior corneal surface 16, a posteriorcorneal surface 14, a lens 20, and a retinal surface 50, in associationwith system 800. System 800 includes a collimated light source 35illuminates a cornea surface 16 and its focal point 15 as shown. Note inthis regard that the eye positioning and stabilization devices havingaspects of the invention, and described with respect to FIGS. 5A-Bprovide for a transparent eye contact member or cup 520, permitting apath for light transmission to and from external and/or internalstructures of eye 10, while the eye is stabilized or positioned.Although the focal point is depicted in front of the lens 20, the focalpoint can focus behind the lens and closer to the retina 50 as welldepending on the power (diopters) of the cornea 12 and/or lens 20. Axis18 is the extension of the collimated light source path 35 through theanterior-posterior axis of an eye and to the retina 50. As long as thecollimated light source travels through or close to the center of thelens, the collimated beam will not be refracted to a great extent. Thisis important in the radiotherapy treatment because radiation travels ina straight line through the eye.

Device 102 includes an imaging device such as a fundus camera or anoptical coherence tomography (OCT) machine. The principles of OCT arefamiliar to those skilled in the art and for the purpose of the presentinvention encompass optical coherence reflectometry and other forms ofoptical interferometry. Additional imaging devices contemplated by thepresent invention include CT Scan, MRI, A- or B-scan ultrasound, acombination of these, or other ophthalmic imaging devices such as ascanning laser ophthalmoscope.

In FIG. 8B, a video image 104 is depicted of a frontal (X-Y) view of theeye 10 in the configuration shown in FIG. 8A. Point 55 represents focalspot 15 as viewed on an imaging monitor 104 using an imaging device 102which can detect the wavelength of light from the collimated lightsource 108. Limit 42 is a pupil in FIG. 8B. Region 30 is a circle, thecenter of which coincides with the center of the limbus 26. Collimatedlight source 108 can be positioned in the X-Y axis so that the center ofits reflection 55 coincides with the center 30 of the limbus 26. Thelimbus of an eye is readily imageable; to the extent the limbus 26 isimageable with the same camera as the reflection of the collimated lightsource 12, both centers can be aligned in the X-Y axis. With suchalignment, intersection of the reference axis 18 with the retina can bedetermined.

In some embodiments, a treatment axis may be defined off-set from thereference axis 18. The treatment axis may be parallel to the referenceaxis, selected so that the target is its intersection with the retina.Treatment beams may then be positioned with respect to the treatmentaxis, for example, at selected angles of rotation about the treatmentaxis.

In certain cases, the axis 18 coincides with a region close to themacula on the retina 50. See FIG. 11 for greater detail. This point canbe called the center of the posterior pole of the eye

FIG. 9A depicts an example where the center of the collimated lightfocus 55 in the X-Y plane, depicted on the video monitor 104, is notcoincident with the center of circle 30 (the center of the limbus 26).FIG. 9B depicts the corresponding case when viewed in theanterior-posterior (Y-Z) axis of the eye, in association with alignmentsystem 900. Focal spot 14 is now off-center or off-axis as shown in FIG.9A in the frontal view. The beam 35 from light source 108 extensionsthrough the eye to the retina and is depicted in FIG. 9B as axis 25.Axis 25 is different from the reference axis 18 in the Y-Z plane; axis25 is an axis in which a collimated light beam would be refracted andits position on the fundus affected by the refraction. Axis 18 is theaxis in this figure which depicts a Y-Z axis which aligns to a pointnear the macula (see FIG. 11 for greater detail).

FIG. 10 depicts a configuration of a device utilized to achieve theresults in FIGS. 8A-9B. An eye 10 is depicted in FIG. 10 in a Y-Z planeand the cornea 12 of the eye depicted on the front surface. A fundusimage (see FIG. 11) can be obtained simultaneously by fundus camera1010. Laser beacon 1015 projects from laser source 1030 to the retinaand can be aligned to the reference axis 18 by aligning it with thecenter of the limbus and simultaneously aligning with its focal spot 15,represented by its reflection in an ordinary imaging camera 102. Beamsplitter 1020 allows deflection of the laser beacon 1015 so that it canbe transmitted through the reference axis of the eye 10. Infrared lightfrom the fundus camera 1010 can pass through the beam splitter 1020 sothat the fundus can be imaged simultaneously with the laser beacon 1015on the fundus image through fundus camera 1010. Beam splitter 1020 canat least partially reflect incident white light so that the camera 102can image the eye. Beam splitter 1022 reflects the laser beacon beam1015 and also at least partially transmits white light so that it canimage the front of the eye in the X-Y plane; that is, the plane on thefront of the eye. The system also includes an X-Y position device whichenables the laser beacon 1015 to be moved to different positions alongthe X-Y axis on the front of the eye. A position sensing element (PSD)can also be included in the path of the laser beacon or using anadditional beam splitter to detect movement or stability over time ofthe beacon. Imaging software integrated with, or linked to, the camera102 can allow stability of the eye 10 to be quantified over time aswell.

FIG. 11A depicts a fundus image 1105 obtained with the system in FIG. 10when the focus of the laser beacon and the laser beacon spot entry arealigned on the center of limbus. The projection of the laser beacon tothe fundus 1105 is the point of intersection of the reference axis withthe retina 1130, and in this embodiment coincides with the approximatecenter of the optical or geometric axis of the eye. For reference, theoptic disc 1110 and the macula/fovea 1120, or center of visual acuity,is shown and is set at a small offset “d” from the reference axisdepicted by the beacon 1130. FIG. 11B depicts an illustration of the eyerepresented in FIG. 12B where the beacon 1130 is not aligned with thecenter of the limbus.

FIG. 12A depicts a summary of the methodology adapted to be used in asystem to deliver radiation therapy to the macula of a patient.Alignment system 1200 is used to obtain a fundus image as shown in FIG.12B. A three-dimensional OCT, or another instrument which can measuredistances quantitatively on the retina, image 1210 is obtained so as toquantify distances between the optic nerve and fovea. The 3D OCT image1210 can be mapped and registered to the fundus image shown in FIGS.11A-B. Such registering allows for the fundus image with the laserbeacon on the reference axis to be scaled for actual distances 1230(a,b,c in FIG. 12B). Axial length measurement 1220 enables the 3D OCT or2D OCT to be scaled for actual distances because these instruments relyon axial length to determine quantitative measurements of theseparameters. Once the measurements are complete 1230, the limbus andcornea of the eye are registered to the macula both in the X-Y plane andin the Z plane. The laser beacon focus at a depth in the eye and itsrelationship to the sclera and limbus can be used in combination withmetrics on the fundus to deliver radiation therapy.

FIG. 13A depicts an x-ray therapy beam 1310 traveling through an eye1300 at an angle 1320. These x-ray beams 1310 are referenced at angles1320 to axis 1330. Depending on the intended target tissue of treatment,axis 1330 may be the optical axis, the geometric axis, or another axisdefined as the treatment axis.

In FIG. 13B, the radiation therapy center 1365 is centered aboutgeometric or optical axis 1360. With the physical metrics determined asdiscussed above in reference to FIGS. 12A-B, the relationship betweenthe center of the limbus, the geometric or optical axis relative to thecenter of the limbus, and the macula are known.

FIG. 13C depicts the center of radiation therapy 1375 coincident withthe macula 1370 and not the geometric or optical axis 1360. In thisradiotherapy planning system, the laser focus through the cornea incombination with the centering of the laser pointer on the center of thelimbus enable a virtual fiducial, or surrogate, for the position of themacula, and therefore, allow the angles of the radiotherapy beams totriangulated to the macula without visualization. The system cansimilarly be used to calibrate a lens or other ocular contact devicethat a patient may wear for delivery of radiotherapy. In anotherembodiment, a lesion on the retina or a drusen deposit can be registeredto the front of the eye.

FIG. 14 depict a method 1475 to use the system of the current disclosureto obtain the relationship between the center of the limbus, the opticalaxis of the eye, and the position a beam travels through the limbusrelative to these positions when a patient fixates on an object. Withthese data, the relationship between the optical axis and the visualaxis can be determined for an individual patient. The first step in themethod is to image the laser beacon focus spot 1470, align the laserbeacon focus with the center of the limbus 1472, and observe with thefundus imaging camera 1474 as described above. From this alignment withthe optical/geometric axis, the center of treatment can be maintained inthis position or it can moved 1476 a distance to the fovea or the centerof a lesion, defining a separate treatment axis.

Photoablative Eye Surgery System

Use of the alignment method discussed above is, in one embodiment of theinvention, applied to photoablative eye surgery. This eye surgery systemembodiment of the invention is shown schematically in FIG. 15. Thesystem 1500 can represent a photoablative eye surgery system forreshaping a patient's cornea represented by anterior corneal surface1512. The system can include an OCT component 1510 that emits a probebeam 1514 which passes through beam splitter 1520 and propagates towardsthe eye 1502. The beam is apertured to preferably restrict the probebeam diameter. This is advantageous in that it restricts the probe beamscan over a small lateral dimension resulting in faster detection of theOCT signal. The probe beam is aligned to the reference axis of the eyeby concentric co-alignment of the center 1560 of the limbus 1565 and thefirst Purkinje reflex 850 as discussed in detail above. The system canfurther includes a therapeutic laser component 1530 that emits atherapeutic beam having a beam propagation axis as shown at 1532. Theprobe beam 1514 from OCT component 1510 is co-aligned and coincidentwith therapeutic beam axis 1532 at the corneal surface. The location oftherapeutic beam axis 1532 on the corneal surface during the therapeuticprocedure is controlled by eye tracker 1540 in a manner well known tothose skilled in the art. That is, the motion of the eye due tovoluntary and involuntary movement is monitored in real time tocoordinate the ablation of the cornea with the therapeutic beam.

The eye tracker 1540 includes at least one image capture device, such asa camera, to at least track the eye in real time. The image capturedevice can detect the position of the eye and relate the direction ofthe laser system to the position of the eye. An optional displaydirected to the operator of the laser system can depict the position ofthe laser device in real time in some embodiments. In some embodiments,the image capture device detects the position of the eye, and digitizingsoftware is used to track the position of the eye. The eye is meant toremain within a preset position, or treatment field, which cancorrespond to the edges of the limbus. When the eye deviates beyond amovement threshold, a signal can be sent to the laser device. Movementthreshold includes a degree or measurement that the eye is able to moveand remain within the parameters of treatment without shutting the laserdevice off. In some embodiments, the movement threshold can be measuredin radians, degrees, millimeters, etc. The laser source is turned offwhen the eye is out of position beyond the movement threshold, and thelaser source is turned on when the eye is within the movement threshold.In some methods of setting the movement threshold, a treatingprofessional delimits the edges of the limbus and treatment planningsoftware then registers the edges of the limbus. If the limbus of theeye moves away from the delimited edge limit, a signal is sent to thelaser device to shut down.

Radiotherapy System

In another embodiment of the invention, the alignment method is utilizedto define an ocular axis of interest which intersects the retina at aretinal target region near the macula, and combined with a therapeutictreatment scheme in which a radiotherapy device is aligned to a needleplaced at least partially through the sclera and even into the vitreousof the eye. A light guide, or pointer, can be placed into or coupledwith the needle to illuminate the retina with a collimated light source.The needle and light guide can be stabilized within the sclera so thatthe collimated light source is stable on the retinal target region. Theradiotherapy device can then be aligned with the needle to deliverradiation in a straight line along the needle and along the light guidepath and to the desired retinal target region. With this treatmentscheme, small regions of the retina can be precisely targeted.

The radiotherapy system used in combination with the alignment methodsdescribed above can be configured to deliver anywhere from about 1 Gy toabout 40 Gy during a treatment period, or from about 10 Gy to about 20Gy during a treatment period, to regions of the eye including, but notlimited to, the retina, sclera, macula, optic nerve, the capsular bag ofthe crystalline or artificial lens, ciliary muscles, lens, cornea, canalof schlemm, choroid, and conjunctiva. In some embodiments, the systemcan be configured to deliver from about 15 Gy to about 25 Gy during atreatment period. In some embodiments, the system 10 is capable ofdelivering x-ray therapy in any fractionation scheme (e.g., about 1 Gyper day, about 5 Gy per day, about 10 Gy per month, or about 25 Gy peryear), as the treatment planning system can retain in memory and recallwhich regions had been treated based on the unique patient anatomicaland disease features. These features and previous treatments are storedin the treatment database for future reference.

The system can also deliver different photon energies depending on thedegree of disease or the region of the eye being treated. For example,the x-ray generation tube can deliver photons with photon energiesranging from about 20 keV to about 40 keV, to about 60 keV, or to about100 keV. It may be desirable to use photons with photon energies rangingfrom about 20 keV to about 50 keV for structures in the anterior portionof the eye because photons with these photon energies will penetrateless. It may be desirable to utilize photons with photon energiesranging from about 60 keV to about 100 keV or greater for structures inthe posterior region of the eye for greater penetration to the retina.In some embodiments, the x-ray generation tube can emit photons withphoton energies from about 10 keV to about 500 keV, from about 25 keV toabout 100 keV, from about 25 keV to about 150 keV, from about 40 keV toabout 100 keV, or any combination of ranges described above or herein.In some embodiments, selection of the photon energy can be based ondiagnostic calculations, which can include a model of the eye createdfrom anatomic data taken from the actual eye of the patient to betreated. The treating medical practitioner can choose the beam energiesbased on the disease and then set the machine to the desired energylevel. In some embodiments, the system can receive input from themedical practitioner relating to the type of disease, and the energylevel can be preset, which can also be subject to modification by themedical practitioner.

Treatment Methods

Thus, the alignment devices and methods described above are useful incombination with numerous treatment devices and compositions to treat awide variety of conditions of the eye of a subject. Sources of treatmentenergy, such as electromagnetic energy emitting devices, can be utilizedto implement corneal and/or non-corneal manipulations. According to thearchitectures and techniques of some embodiments of the invention, thesource or sources (when utilized in combination) can be activated todirect energy onto and/or into parts of the eye, such as the conjunctivaand sclera to treat conditions such as presbyopia, wherein the energyaffects at least one property of the eye and results in an enhancementin a property of the eye.

In some embodiments of the invention, focusing disorders such as myopiaand hyperopia are treated. Myopia, or nearsightedness, relates to aneyesight refractive abnormality whereby distant objects appear blurredas a result of rays of light entering the eye being brought to focus infront of the retina. Hyperopia, or farsightedness, on the other hand,relates to an eyesight refractive abnormality whereby near objectsappear blurred or fuzzy as a result of light rays being brought to focusbehind the retina.

In addition to myopia and hyperopia, presbyopia is typically associatedwith a person's lack of capacity to focus at near distances and whichtends to develop and progress with age. Regarding this progression,presbyopia is thought to advance as the eye progressively loses itsability to accommodate or focus sharply for near vision with increasingage of the person. Accordingly, the condition of presbyopia generallysignifies a universal decrease in the amplitude of accommodation of theaffected person.

Myopia and hyperopia can be treated surgically using techniquesincluding corneal interventions, such as reshaping a surface curvatureof the cornea located inside of the limbus area, and non-cornealmanipulations, such as altering properties of the sclera (which islocated outside of the limbus area), ciliary muscle, zonules, or lens.An example of the former treatment includes ablating the surface of thecornea itself to form a multifocal arrangement (e.g., distance vision inone eye and reading vision in another eye according to a treatment planreferred to as monovision) facilitating viewing by a patient of bothnear and far objects. An example of the latter treatment includesintroducing kerfs into portions of the sclera to thereby increaseaccommodation. Non-corneal interventions typically include temporarilyremoving or pulling back the subject's conjunctiva, using forceps andscissors and/or one or more of scalpels, cautery, plasma, and lasermethods, followed by the actual non-corneal manipulations (e.g., formingkerfs in the sclera). After completing the kerfs, the conjunctiva isthen typically sutured back into position.

Electromagnetic energy devices may include, for example, lasers emittinga wide range of wavelengths, such as lasers having wavelengths ranging,for example, from about 0.2 microns to about 3.1 microns. Exemplarylaser beam sizes can range from about 0.005 mm up to about 1.0 mm, or2.0 mm. Exemplary laser energy per pulse values can range from about 0.1mJ to about 50 mJ depending on, for example, the pulse duration and thelaser beam spot size. Typical pulse laser widths may range from about150 nanoseconds to about 1000 microseconds. The areas to be treated canbe pre-traced with a vascular laser or long pulse Er, Cr:YSGG, or longpulse Er:YAG, to minimize bleeding.

In one embodiment of the invention, radiotherapy is administered.Radiotherapy is particularly useful for treating macular degeneration.Macular degeneration is a condition where the light-sensing cells of themacula, a near-center portion of the retina of the human eye,malfunction and slowly cease to work. Macular degeneration is theleading cause of central vision loss in people over the age of fiftyyears. Clinical and histologic evidence indicates that maculardegeneration is in part caused by or results in an inflammatory processthat ultimately causes destruction of the retina. The inflammatoryprocess can result in direct destruction of the retina or destructionvia formation of neovascular membranes which leak fluid and blood intothe retina, quickly leading to scarring.

Radiotherapy can be used in combination with other therapeutics for theeye. Radiotherapy can be used to limit the side effects of othertreatments or can work synergistically with other therapies. Forexample, radiotherapy can be applied to laser burns on the retina or toimplants or surgery on the anterior region of the eye. Radiotherapy canbe combined with one or more pharmaceutical, medical treatments, and/orphotodynamic treatments or agents. For example, radiotherapy can be usedin conjunction with anti-VEGF treatment, VEGF receptors, steroids,anti-inflammatory compounds, DNA binding molecules, oxygen radicalforming therapies, oxygen carrying molecules, porphyrynmolecules/therapies, gadolinium, particulate based formulations,oncologic chemotherapies, heat therapies, ultrasound therapies, andlaser therapies.

In some embodiments, radiosensitizers and/or radioprotectors can becombined with treatment to decrease or increase the effects ofradiotherapy, as discussed in Thomas, et al., Radiation Modifiers:Treatment Overview and Future Investigations, Hematol. Oncol. Clin. N.Am. 20 (2006) 119-139; Senan, et al., Design of Clinical Trials ofRadiation Combined with Antiangiogenic Therapy, Oncologist 12 (2007)465-477; the entirety of both of these articles are incorporated byreference herein. Some embodiments include radiotherapy with thefollowing radiosensitizers and/or treatments: 5-fluorouracil,fluorinated pyrimidine antimetabolite, anti-S phase cytotoxin,5-fluorouridine triphosphate, 2-deoxyfluorouridine monophosphate(Fd-UMP), and 2-deoxyfluorouridine triphosphate capecitabine, platinumanalogues such as cisplatin and carboplatin, fluoropyrimidine,gemcitabine, antimetabolites, taxanes, docetaxel, topoisomerase Iinhibitors, Irinotecan, cyclo-oxygenase-2 inhibitors, hypoxic cellradiosensitizers, antiangiogenic therapy, bevacizumab, recombinantmonoclonal antibody, ras mediation and epidermal growth factor receptor,tumor necrosis factor vector, adenoviral vector Egr-RNF (Ad5.Egr-TNF),and hyperthermia. In some embodiments, embodiments include radiotherapywith the following radioprotectors and/or treatments: amifostine,sucralfate, cytoprotective thiol, vitamins and antioxidants, vitamin C,tocopherol-monoglucoside, pentoxifylline, alpha-tocopherol,beta-carotene, and pilocarpine.

Antiangiogenic Agents (AAs) aim to inhibit growth of new blood vessels.Bevacizumab is a humanized monoclonal antibody that acts by binding andneutralizing VEGF, which is a ligand with a central role in signalingpathways controlling blood vessel development. Findings suggest thatanti-VEGF therapy has a direct antivascular effect in human tissues. Incontrast, small molecule tyrosine kinase inhibitors (TKIs) preventactivation of VEGFRs, thus inhibiting downstream signaling pathwaysrather than binding to VEGF directly. Vascular damaging agents (VDAs)cause a rapid shutdown of established vasculature, leading to secondarytissue death. The microtubule-destabilizing agents, includingcombretastatins and ZD6126, and drugs related to5,6-dimethylxanthenone-4-acetic acid (DMXAA) are two main groups ofVDAs. Mixed inhibitors, including agents such as EGFR inhibitors orneutralizing agents and cytotoxic anticancer agents can also be used.

Thus, the system of the present invention can be used in someembodiments to provide radiotherapy treatment. A treatment axis whichprovides a reference about which application of the radiation beams areapplied can be coupled to or aligned with a system axis of theradiotherapy system, about which an x-ray source can be positioned,e.g., by being rotated. The x-ray source can rotate about the systemaxis of the radiotherapy device, about which the x-ray source can berotated. The x-ray source can rotate about the system axis with orindependent from an imaging subsystem and its corresponding axis. Withthe treatment axis aligned with the system axis, and with the couplingdevice engaging the eye, trajectories of the radiation beams can bedetermined to direct the radiation beams to be coincident with thetarget tissue of the eye of the subject. The defined space of thetreatment axis, the system axis, the location of the coupling device,and the location of the x-ray source provides a confined coordinateframe that can be used, for example, for directing orientation andadministration of the radiation beams.

In one embodiment of the invention, radiodynamic therapy isadministered. Radiodynamic agents can be administered eithersystemically or into the vitreous; the region in the eye to be treatedis then directly targeted with radiotherapy as described above. Thetargeted region can be precisely localized using the device of theinvention and/or in combination with an eye model, and then radiationcan be precisely applied to that region. Beam sizes of about 1 mm orless can be used in radiodynamic therapy to treat ocular disorders ifthe target is drusen for example. In other examples, the beam size isless than about 6 mm.

It is further contemplated that the system of the present invention canbe utilized to treat a variety of types of cancer of the eye. Exemplarycancer treatments are described below. Intraocular melanoma starts frompigment cells called melanocytes, which are found in the part of the eyeknown as the uvea. The uvea includes the iris, which forms the coloredpart of the eye; the ciliary body, which helps change the shape of thelens inside the eye so that it can focus; and the choroid, which is avery deep layer of the eye. Though it is uncommon, uveal melanoma is themost common primary eye tumor in adults; approximately 1200 people arediagnosed with the disease each year in the United States. Factorsassociated with the disease's development include light skin color,environmental exposure and genetic predisposition. If the melanomabegins in the iris, it may appear as a dark spot on the eye. However, ifit begins in the ciliary body or choroid, symptoms may appear as visionproblems, if at all. In these cases, the disease is usually detectedduring a routine examination. Chances of recovery and response totreatment depend on the location of the melanoma and whether it hasspread. Posterior uveal tract melanomas (those cancers arising from theciliary body or the choroid—the deeper parts of the eye) are typicallymore malignant, with a five-year mortality rate of 30% when the tumorhas spread to areas outside of the eye. Anterior uveal tract melanomas(those arising from the iris) have a 2% to 3% mortality rate over fiveyears. Thus, in one embodiment of the invention, intraocular melanoma istreated using the system of the invention.

Standard treatment for intraocular melanoma typically includes surgicalremoval of the eye, or enucleation. Because of this procedure's effecton a patient's appearance, possible diagnostic uncertainties and thepotential for the cancer to spread, alternative treatments have beenintroduced. These treatments include radiation with radioactive plaques,laser photocoagulation, transpupillary thermotherapy and cryotherapy.Also contemplated is proton beam therapy which has the ability toprecisely target eye tumors without causing any serious damage tohealthy tissue surrounding the eye.

Choroidal metastasis occurs when cancer spreads to the choroidal layerof the eye from another primary site, like the breast. In thesesituations, the goal of treatment is to improve the patient's quality oflife by preserving vision and preventing removal of the eye.Chemotherapy, external beam radiation therapy and proton therapy incombination with the system described above are contemplated by thepresent invention for the treatment of choroidal metastasis such thatthe therapeutic treatment allows for retention of the eye, achieves ahigh probability of local control, and helps avoid vision loss and pain.

Retinoblastoma is an uncommon childhood cancer. It begins in the retina,and accounts for about 3% of cancers in children younger than 15years—about 4 cases per million. It most often occurs before the age oftwo, with 95% of retinoblastoma diagnosed before the age of five. Thetumor may affect one eye (about 75% of cases), or both eyes (25% ofcases). More than 90% of retinoblastoma that does not spread beyond theeye will be cured. Retinoblastoma is sometimes caused by an inheritedgene mutation; when it occurs in both eyes, it is always the result of agene mutation. Treatment of retinoblastoma in accordance with thepresent invention contemplates a multidisciplinary approach, andinvolves treating the cancer as well as retaining vision. If the tumoris especially large, or if there is little expectation of retainingnormal vision, surgery may be considered. Other options includecryotherapy, photocoagulation, chemotherapy, and radiation therapy.External beam radiation therapy with protons has been used in selectcases to control tumors. Proton therapy in combination with the systemof the invention is also contemplated by the present invention.

Choroidal hemangiomas are benign vascular tumors that are usually wellcontained, and may cause a decrease in visual abilities. Treatment ofchoroidal hemangiomas is meant to reduce fluid collection under theretina and decrease the size of the tumor. Standard treatment involveslaser photocoagulation, which successfully reattaches the retina, butmay not always completely destroy the tumor. In recent years,radioactive plaque treatment and proton beam radiation treatments havebeen used. Proton beam therapy shares the precise tumor targetingability of radioactive plaques, and is therefore contemplated for usewith the system of the present invention.

In addition to the cancer treatment methods described above, theinvention also contemplates aligning and manipulating the eye so as tomove critical structures away from the treatment axis to delivertherapeutic amounts of radiation to tumors outside, but near, the eye.Thus, in one embodiment of the invention, the system is used to positionthe eye for the treatment of extraocular conditions. In one embodimentof the invention, the device described above is utilized in combinationwith other therapeutics for the eye. For example, one or more therapytreatments such as cryotherapy, photocoagulation, chemotherapy, andradiation therapy can be utilized in combination with the system of thepresent invention to provide therapeutic treatment of the eye.

From the foregoing, it can be seen how various objects and features ofthe invention are met. While certain aspects and embodiments of thedisclosure have been described, these have been presented by way ofexample only, and are not intended to limit the scope of the disclosure.The methods and systems described herein may be embodied in a variety ofother forms without departing from the spirit thereof. All publicationsand patents cited herein are expressly incorporated herein by referencefor the purpose of describing and disclosing systems and methodologieswhich might be used in connection with the invention.

1.-47. (canceled)
 48. A system for defining a reference axis of apatient's eye in an external coordinate system, comprising: an eye guideadapted to be coupled to the patient's eye; a light source for directinga light beam on a reflective surface associated with the patient's eye;an imaging system for recording an image of a limbus of the patient'seye and an image formed by a reflection of the light beam on thereflective surface; and a guide-alignment assembly configured to adjustthe eye guide until a position of the reflection is coincident with acenter of the limbus.
 49. The system of claim 48, wherein the reflectivesurface is a cornea of the patient's eye.
 50. The system of claim 48,wherein the reflective surface a reflective surface of a contact memberfor positioning on a surface of the patient's eye.
 51. The system ofclaim 48, wherein, when the position of the reflection is coincidentwith the center of the limbus, an axis normal to a cornea at a cornealcenter defines the reference axis.
 52. The system of claim 48, wherein aguide-alignment assembly is configured to adjust the patient's eye byadjusting the eye guide.
 53. The system of claim 48, wherein the imagingsystem comprises a camera.
 54. The system of claim 48, wherein theimaging system comprises a photodetector.
 55. The system of claim 48,further comprising a processor operatively connected to the imagingsystem and the guide-alignment assembly.
 56. The system of claim 48,further comprising a processor configured to, from the image of thelimbus, determine the center of the limbus of the patient's eye in theexternal-coordinate system.
 57. The system of claim 48, furthercomprising a processor configured to, from the image of the reflectionof the light beam on the reflective surface, determine when the positionof the reflection image is coincident with the center of the limbus. 58.The system of claim 48, further comprising a processor configured to:determine from the image of eye guide and the sclera/cornea boundary,any variation from true centering of the eye guide on the patient's eye,if variation from true centering is determined, construct a coordinatetransform between the actual and centered positions of the eye guide,with the eye guide moved to and held at its aligned position, andapplying the coordinate transform if necessary, determine the positionof the eye with respect to the reference axis, determine a treatmentaxis or axes along which a therapeutic beam will be aimed at a targetregion of the eye, and
 59. The system of claim 48, further comprising aprocessor configured to generate positioning signals for positioning adiagnostic or therapeutic device at a selected position and angle withrespect to the reference axis.
 60. The system of claim 48, furthercomprising a display monitor for displaying to a user, an image of thepatient's eye and attached eye guide, information about the extent ofalignment between the eye guide and light beam, and a virtual image ofthe reference axis.
 61. The system of claim 48, further comprising animage processor, wherein the processor is configured to fit the image ofthe limbus to a circle and determine the center of the circle.
 62. Thesystem of claim 48, wherein the eye guide is configured to be stabilizedon the eye by an application of negative pressure between the eye guideand eye.
 63. The system of claim 48, wherein the eye guide comprises aneye-contact portion configured to operatively contact an anteriorsurface of the eye, and a support portion operatively engageable to theeye-contact portion, and wherein eye-contact portion and the supportportion are configured to engage releasably, the release being uponvoluntary or involuntary motion by the patient
 64. The system of claim48, wherein the guide-alignment assembly comprises an external armpivotally attached to the eye guide to hold the eye at a position inwhich the eye guide is aligned with the reference axis.
 65. The systemof claim 48, further comprising a head restraint configured to stabilizethe patient's head.
 66. The system of claim 48, further comprising anX-ray device configured to emit an X-ray beam.